PDGF-C and PDGF-D signaling in vascular diseases and animal models
Erika Folestad
a, Anne Kunath
b, Dick Wågs€ater
b,*aDivision of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden bDivision of Drug Research, Department of Medical and Health Sciences, Link€oping University, Link€oping, Sweden
a r t i c l e i n f o
Article history: Received 31 August 2017 Received in revised form 14 November 2017 Accepted 22 January 2018 Available online 14 February 2018 Keywords:
Aneurysm Atherosclerosis Growth factor Myocardial infarction Smooth muscle cells
a b s t r a c t
Members of the platelet-derived growth factor (PDGF) family are well known to be involved in different pathological conditions. The cellular and molecular mechanisms induced by the PDGF signaling have been well studied. Nevertheless, there is much more to discover about their functions and some important questions to be answered. This review summarizes the known roles of two of the PDGFs, PDGF-C and PDGF-D, in vascular diseases. There are clear implications for these growth factors in several vascular diseases, such as atherosclerosis and stroke. The PDGF receptors are broadly expressed in the cardiovascular system in cells such asfibroblasts, smooth muscle cells and pericytes. Altered expression of the receptors and the ligands have been found in various cardiovascular diseases and current studies have shown important implications of PDGF-C and PDGF-D signaling in fibrosis, neovascularization, atherosclerosis and restenosis.
© 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Cardiovascular disease accounts for a large proportion of deaths, and the disease's development depends on a pathological change in a large number of factors. Infiltrated leukocytes and activated vascular cells such as endothelial cells, smooth muscle cells (SMC) andfibroblasts secrete different growth factors, cytokines and other inflammatory factors that facilitates a local low grade inflammation resulting in tissue remodeling. Among these factors, the platelet-derived growth factors (PDGF) play an important role involving multiple mechanisms responsible for vascular pathologies such as atherosclerosis, restenosis, aortic aneurysm and pulmonary arterial hypertension, resulting in ischemia, myocardial infarction and stroke as example.
The PDGF family is probably one of the best studied growth factor systems. The PDGF family consists of four members; the classical A and B, but also the novel C and PDGF-D. The classical PDGFs are well studied, however, even though it was more than 15 years ago, since the novel PDGF-C and PDGF-D were discovered, they have not yet been studied in detail in the context of vascular and cardiovascular disease. The two were discovered in 2000 (Li et al., 2000) and 2001 (Bergsten et al., 2001;
LaRochelle et al., 2001). This review will focus on and summarize the literature of PDGF-C and PDGF-D, and their receptors PDGFR-
a
and PDGFR-b
, in the field of vascular physiology and pathology, including angiogenesis and vascular disease.2. PDGF structure and signaling
The structure and signaling of the PDGF family has been described and reviewed elsewhere in detail, therefore it is only summarized in brief in this review. Members of the PDGF family binds to and signals through the PDGF receptors (Fig. 1). They are tyrosine kinase receptors, which are expressed in two different forms, PDGFR-
a
and PDGFR-b
, that encode a transmembrane pro-tein with an extracellular ligand-binding domain and an intracel-lular tyrosine kinase domain (Heldin and Westermark, 1999; Kazlauskas, 2017; Westermark et al., 1989, 1990). These two re-ceptor isoforms dimerize upon ligand binding, which leads to one of the three possible receptor combination -aa
, -ab
and -bb
. The dimerization results in receptor autophosphorylation on tyrosine residues in the intracellular domain (Heldin and Westermark, 1999; Kelly et al., 1991; Westermark et al., 1989, 1990). Autophosphor-ylation further activates the receptor kinase and docking sites for downstream signaling molecules and modulation of different pathways (Kazlauskas and Cooper, 1989; Reigstad et al., 2005; Westermark et al., 1989, 1990).PDGF-AA can bind the PDGFR-
aa
and PDGF-BB binds all forms, (i.e., PDGFR-aa
, PDGFR-ab
and PDGFR-bb
) (Andrae et al., 2008; * Corresponding author. Link€oping University, entrence 68, 581 85, Link€oping,Sweden.
E-mail address:Dick.Wagsater@liu.se(D. Wågs€ater).
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Molecular Aspects of Medicine
j o u r n a l h o me p a g e : w w w . e l s e v i e r . c o m / l o ca t e / m a m
https://doi.org/10.1016/j.mam.2018.01.005
Heldin and Westermark, 1999; Raines, 2004; Seifert et al., 1989). The heterodimer PDGF-AB can bind PDGFR-
aa
and PDGFR-ab
.As for PDGF-A and PDGF-B, PDGF-C and PDGF-D also exert their biological functions by binding to these receptors (Andrae et al., 2008; Fredriksson et al., 2004; Heldin and Westermark, 1999). PDGF-CC preferentially binds to and signals through PDGFR-
a
homodimers (Li and Eriksson, 2003; Li et al., 2000), while PDGF-DD mainly binds to PDGFR-b
homodimers (Bergsten et al., 2001; LaRochelle et al., 2001). The signaling effects of PDGF-A and PDGF-B have been extensively investigated, and since PDGF-C and D also bind these receptors, one could predict similar effects.Due to their highly conserved cysteine knot motif, PDGF-C and PDGF-D belong to the PDGF/vascular endothelial growth factor (PDGF/VEGF) family and reside in humans on chromosome 4 and 11, respectively (Uutela et al., 2001). In addition to having the common structure of classic PDGFs (i.e. PDGF-A and PDGF-B), PDGF-C and PDGF-D both have an additional unique N-terminal CUB domain (Complement subcomponents c1r/c1s, Urchin epidermal growth factor (EGF)-like protein and Bone morphogenic protein 1), which binds to the extracellular matrix to prevent diffusion (Andrae et al., 2008; Bergsten et al., 2001; Bork and Beckmann, 1993; LaRochelle et al., 2001; Li et al., 2000). The CUB domain blocks the receptor binding of the C-terminal growth factor domain and needs to be cleaved extracellularly to make the growth
factor domain active and induce receptor signaling (Bergsten et al., 2001; LaRochelle et al., 2001; Li et al., 2000). The hinge regions of PDGF-C and PDGF-D are between the CUB domain and the growth factor domain and contain cleavage sites for proteolytic removal of the CUB domain before receptor binding. PDGF-C and PDGF-D occur as homodimers (PDGF-CC and PDGF-DD), which are secreted in their full-length form before proteolytic activation. The extracellular cleavage is performed by serine proteases. Plasmin and tissue plasminogen activator (tPA) cleave PDGF-C (Fredriksson et al., 2004, 2005; Gilbertson et al., 2001; Li et al., 2000), while plasmin, urokinase plasminogen activator (uPA) and matriptase were found to cleave PDGF-D (Ehnman et al., 2009; Reigstad et al., 2005; Ustach et al., 2010; Ustach and Kim, 2005).
Riehle and colleagues used tPA knockout mice crossed with transgenic mice overexpressing PDGF-C and showed that cleaved PDGF-C levels remained high (Riehle et al., 2014), indicating that other proteases might also be involved in cleavage of PDGF-C. A study also showed that using matriptase to remove the CUB domain increases the binding of PDGF-DD to extracellular matrix, whereas the cleavage of the growth factor domain reduces the association of PDGF-D and extracellular matrix and can act as dominant-negative ligand that prevents PDGF-B mediated PDGFR-
b
activation (Huang and Kim, 2015). Interestingly, recent findings show that PDGFR signaling can be modified by neuropilin-1, which binds PDGF-D and Fig. 1. Simplified schematic overview demonstrating PDGF processing, secretion and receptor binding from both in vitro and in vivo studies. Furin is mainly responsible for the intracellular cleavage of propeptides in PDGF-A and PDGF-B that can bind to the extracellular matrix or diffuse if the c-terminal retention motif is cleaved. PDGF-C and PDGF-D are secreted in inactive forms and are activated by tPA and uPA or matriptase, respectively.functions as a co-receptor in PDGF-D/PDGFR-
b
signaling (Muhl et al., 2017).PDGF ligand signaling is involved in several pathophysiological conditions. Detailed expression patterns of the individual PDGF li-gands and receptors are complex and the in vitro and in vivo expression have been found to differ. PDGFs are stored and released by
a
-granules of activated platelets, but can be further secreted by macrophages,fibroblasts, vascular SMCs, endothelial cells, epithe-lial cells and gepithe-lial cells (Andrae et al., 2008; Demoulin and Essaghir, 2014; Huang and Kim, 2015). PDGFs act on neighboring cells pri-marily in a paracrine manner (Andrae et al., 2008).PDGF-C promotes migration and proliferation of macrophages (Boor et al., 2010; Wågs€ater et al., 2009), endothelial cells (Li et al., 2005) and vascular SMCs (Crawford et al., 2009). Through its effects on multiple cell types, PDGF-C has been shown to have a critical role in embryonic development (Ding et al., 2000),fibrosis (Ponten et al., 2003), wound healing (Grazul-Bilska et al., 2003) and angiogenesis (Cao et al., 2002; Crawford et al., 2009; Li et al., 2005). PDGF-D is mainly expressed in endothelial cells and SMCs (Gladh et al., 2016; Karvinen et al., 2009; Ponten et al., 2005; Wågs€ater et al., 2009). It also plays a role in wound healing (Uutela et al., 2004), fibrotic processes, various cancers (Andrae et al., 2008; Cortez et al., 2016; Ponten et al., 2005; Wang et al., 2010) and cardiovascular diseases such as arteriosclerosis (Hsu and Smith, 2012; Karvinen et al., 2009).
3. PDGF receptors in vascular disease
The PDGFRs are broadly expressed in the cardiovascular system in cells of mesenchymal origin, such asfibroblasts, SMCs and per-icytes. Consequently, PDGF receptor signaling is important for the proper development and maintenance of the vascular and cardio-vascular system. This was shown in knockout mouse studies, as both PDGFR null mice phenotypes are embryonically lethal (Andrae et al., 2008). PDGFR-
a
signaling is indispensable in organogenesis (Soriano, 1997), and PDGFR-b
signaling is crucial for proper devel-opment of the vascular system. PDGFR-b
is mainly expressed by pericytes and its signaling is necessary for proper recruitment of vascular SMC and pericytes (Leveen et al., 1994). PDGF receptor activation has been particularly linked to angiogenesis where PDGFR-b
expression especially correlates with increased vascu-larity and maturation of the vascular wall (Cao et al., 2002; Laschke et al., 2006; Raica and Cimpean, 2010).Many signaling pathways with essential functions in normal physiology are also often key players in the development and progression of diseases. Dysregulation of PDGF receptor activity is seen in a number of common pathological conditions such as atherosclerosis, which is the main underlying cause of cardiovas-cular diseases, including myocardial infarction and stroke (Hu and Huang, 2015; Raines, 2004). Altered expression of PDGFR-
a
and PDGFR-b
have been found in cardiovascular diseases such as myocardial infarction and stroke and in vascular diseases such as aortic aneurysm and pulmonary arterial hypertension (Hu and Huang, 2015). In general, two types of cells appear to respond in a pathological fashion to increased PDGF receptor activity, namely SMCs and fibroblasts. As a response to the enhanced receptor expression and signaling, these cell types increase in proliferation, differentiation, apoptosis, migration and invasion, which promotes vessel wall pathologies andfibrotic tissue scarring. PDGFR-b
seems to be the PDGF receptor principally involved in vascular pathology. The role for PDGFR-a
signaling is to stimulate various types of mesenchymal cell/fibroblast-driven pathological processes, includingfibrotic responses. In infarcted heart, expression of the PDGF receptors are augmented in the myocardium in both early and late stages (Zhao et al., 2011). Blocking of PDGF receptor activityin infarcted heart reduces the interstitialfibrosis (Liu et al., 2014). 3.1. Atherosclerosis
A major risk factor for developing vascular and cardiovascular disease is atherosclerosis, a process in which lipid-containing pla-ques are slowly formed in the vascular wall followed by in flam-mation that stimulates SMCs to proliferate and migrate. The cellular changes in the vascular wall eventually lead to vessel occlusion (Raines, 2004). In atherosclerosis expression of both PDGFR-
a
and PDGFR-b
are widely upregulated in the vessel wall, and they are expressed by vascular SMCs and macrophages. PDGFR-b
is more abundantly expressed than PDGFR-a
, and PDGFR-b
signaling also appears to be the driving force in the atherogenic process where the receptor activation induces leukocyte migration (Andrae et al., 2008; Karvinen et al., 2009; Raines, 2004; Wågs€ater et al., 2009). Furthermore, PDGFR-b
expression is also induced during monocyte-to-macrophage differentiation, and strongly expressed in fatty streaks. Active vascular SMCs play a central role because they proliferate and contribute to the thickening of the vascular wall. Activation of vascular SMCs from a contractile to synthetic phenotype of vascular SMCs is also associated with increased PDGFR-b
expression and signaling (Hansson, 2005; He et al., 2015). Furthermore, PDGFR-b
antibodies (Sano et al., 2001) or PDGFR blocking kinase inhibitor (Kozaki et al., 2002) reduced the athero-sclerotic progression in an atheroathero-sclerotic mouse model.Low-density lipoprotein receptor-related protein 1 (LRP-1) forms a complex with PDGFR-
b
, which gives it an important role in controlling this activation. Boucher and colleagues demonstrated that treatment with the tyrosine kinase inhibitor imatinib blocked activation of LRP-1-induced phosphorylation of PDGFR-b
and reduced the size and area of the atherosclerotic lesions in mice (Boucher et al., 2003).3.2. Restenosis
Restenosis and chronic rejection are vascular diseases that give rise to conditions similar to atherosclerosis. Following blood vessel injury and angioplasty, medial vascular SMCs migrate to the intima, where they proliferate and switch to a synthetic phenotype in a PDGFR-
b
dependent manner, resulting in neointimal hyperplasia (Raines, 2004). PDGFR-a
immunoreactivity is increased in the media of arteries in acute rejection (Tuuminen et al., 2009).PDGF receptor tyrosine kinase inhibitors have inhibitory effects on restenosis after balloon angioplasty (Bilder et al., 1999; Sihvola et al., 1999). Micke and colleagues showed that protein tyrosine phosphatases are important in PDGF signaling in vascular remod-eling (Micke et al., 2009). The adventitial layers of vessels were studied in a rat carotid artery model. PDGFR-
b
were upregulated together with the receptor antagonists density-enhanced phos-phatase-1 (DEP-1) and T-cell protein tyrosine phosphatase (TC-PTP). The mRNA expression of PDGF ligands, PDGFR-b
and protein tyrosine phosphatases DEP-1, TC-PTP, SHP-2 and PTP1B correlated with vascular morphometrics, proliferation and PDGFR-b
activity. 3.3. StrokePDGF signaling is also important in stroke where activation of PDGFR-
a
on perivascular astrocytes is involved in the acute opening of the blood-brain barrier (BBB). In a study it was shown that treatment of mice with the PDGFR antagonist imatinib after an ischemic stroke reduced brain damage by decreasing the cerebro-vascular permeability and hemorrhagic complications (Su et al., 2008, 2009). These data suggested potential new strategies for stroke treatment, and a phase II study showed that imatinib is safeand reduces neurological disability in patients treated with intra-venous thrombolysis after an ischemic stroke (Wahlgren et al., 2017). PDGFR-
b
also play important roles in stroke. In adult normal matured brain PDGFR-b
expression is low. It is, however, gradually induced predominantly in pericytes and fibroblast-like cells in stroke areas after the induction of brain ischemia. After brain ischemia PDGFR-b
mediates various function such as regu-lation of the BBB and tissue repair of infarcted areas (Cai et al., 2017; Nakamura et al., 2016).3.4. Pulmonary arterial hypertension
Pulmonary arterial hypertension is a vascular disease involving endothelial dysfunction and proliferation and migration of vascular SMCs causing increased vascular resistance, which eventually leads to right ventricular failure and death. Increased expression and phosphorylation of PDGF receptor has been correlated with pul-monary arterial hypertension in various experimental animal models (Guignabert et al., 2009; Hu and Huang, 2015) and in humans (Schermuly et al., 2005). The tyrosine kinase inhibitor imatinib was shown to reverse experimental hypertension in ani-mal models of pulmonary arterial hypertension (Schermuly et al., 2005). In a human case of pulmonary arterial hypertension, ima-tinib showed promising preliminary results, but unfortunately some serious adverse events, including subdural hematomas, also occurred (Hoeper et al., 2013; Shah et al., 2015).
3.5. Abdominal aortic aneurysm
An abdominal aortic aneurysm (AAA) is a disease characterized by vascular remodeling, infiltration of inflammatory cells and modulation of vascular SMCs. Expression of PDGFR-
a
and PDGFR-b
has been found in both human and mouse AAAs, and PDGFR-b
is strongly expressed by vascular SMCs (Kanazawa et al., 2005; Vorkapic et al., 2016). Using imatinib to inhibit PDGF receptor activation in an animal model of AAA reduced the expression of phosphorylated PDGFR-b
in aortas and hindered aneurysm for-mation, suggesting that it is beneficial to reduce PDGFR activation in pathological vascular inflammation such as AAA (Vorkapic et al., 2016).3.6. Adipocyte metabolism and angiogenesis
Impaired regulation of the PDGF receptors is also linked to some of the underlying causes of cardiovascular disease such as adult obesity and type II diabetes. In patients with diabetes, increased PDGFR-
b
signaling was found to accelerate the growth of aortic vascular SMCs (Hu and Huang, 2015). Furthermore, PDGFR-b
acti-vation plays a significant role in the development of adipose tissue neovascularization, and targeting PDGFR-b
could be a strategy for preventing obesity and type II diabetes (Onogi et al., 2017).4. PDGF-C and PDGF-D in vascular disease
In healthy vasculature, the expression of PDGF ligands is low or undetectable. Yet, increased expression of all PDGF ligands, including PDGF-C and PDGF-D, are found in many vascular and cardiovascular diseases. Dysregulation of PDGF-D appears to be more prevalent than PDGF-C in classical cardiovascular diseases involving proliferation and differentiation of vascular SMC.Fig. 2
briefly summarizes expression and role of PDGF-C and PDGF-D in vascular wall.
4.1. Atherosclerosis
In the atherosclerotic vessel wall, both PDGF-C and PDGF-D are increased and mainly secreted by endothelial cells, vascular SMCs and macrophages (Karvinen et al., 2009; Raines, 2004; Wågs€ater
et al., 2009). PDGF-D is upregulated in endothelial cells exposed to atheroprone bloodflow and is induced during macrophage dif-ferentiation. PDGF-D is strongly expressed in fatty streaks and its increased expression promotes vascular SMC phenotypic switch by inhibiting expression of multiple SMC genes, including smooth muscle
a
-actin (a
-SMA) and smooth muscle myosin heavy chain (Raines, 2004; Thomas et al., 2009). Furthermore, PDGF-D is upregulated in the intima following angioplasty and has been suggested to be involved in the formation of neointimal hyperplasia induced at vascular injury, and might serve as a target in preventing vascular restenosis (Chen et al., 2005; Raines, 2004). PDGF-C and PDGF-D were upregulated in adventitial layers of vessels in a rat carotid artery model (Micke et al., 2009). As a result of macrophage accumulation, PDGF-C levels increase in the arterial wall, resulting in SMC proliferation (Chen et al., 2014). It was shown that PDGF-C and PDGF-D might play important roles in atherosclerosis by stimulating the activity of matrix metalloproteinase (MMP)-9 and by influencing monocyte migration (Wågs€ater et al., 2009). 4.2. FibrosisPDGF/PDGFR signaling plays essential roles during embryonic development, but its function in adulthood is often unclear and seems to be more detrimental than constructive in human physi-ology, except in wound healing (Chen et al., 2013). PDGF signaling plays a critical role during the proliferation and migration stage of wound healing (Grazul-Bilska et al., 2003). Fibrosis results from the deposition of extracellular matrix primarily by myofibroblasts. PDGFs, in particular PDGF-A and PDGF-B, play an important role in the phenotypic change offibroblasts into myofibroblasts by stim-ulating proliferation and migration (Kinnman et al., 2003; Tangkijvanich et al., 2002).
The link between PDGF and transforming growth factor (TGF)-
b
signaling in the development offibrosis is well described. TGF-b
is overexpressed and regulatesfibroblast differentiation into myofi-broblasts. In addition, the connection of PDGF-C and PDGF-D and TGF-b
has been studied. Chaabane and colleagues demonstrated thefirst link between TGF-b
and PDGF-C and PDGF-D ligands.TGF-b
reduced expression of PDGF-D and induced expression of PDGF-C. PDGF-D was downregulated in a model of lungfibrosis and this correlated with TGF-b
and otherfibrotic growth factors (Chaabane et al., 2014).In another fibrosis model, which used bile duct ligation or induced hepatic fibrosis model, PDGF-D was upregulated and adenoviral PDGF-D gene transfer induced hepatic stellate cell proliferation and liverfibrosis (Borkham-Kamphorst et al., 2015). In vitro stimulation of hepatic stellate cells upregulated expression of TIMP-1, which attenuated MMP-2 and MMP-9 activity whereas levels of collagen I and
a
-SMA were unchanged.Macrophages are also known to play an important role in wound healing (Gilbertson et al., 2001; Glim et al., 2013). PDGF-D affects different stages of wound healing by enhancing recruitment of macrophages in the skin and increasing macrophage accumulation in skeletal muscle, which leads to acceleration of wound healing (Gilbertson et al., 2001; Pierce et al., 1991; Uutela et al., 2004). Anti-inflammatory M2 macrophages have increased mRNA and protein levels of PDGF-C, which is able to induce
a
-SMA expression in fi-broblasts (Glim et al., 2013). In contrast, lack of PDGF-C in M2 macrophages leads to decreaseda
-SMA expression infibroblasts (Glim et al., 2013). Overexpression of PDGF-C could contribute tofibrosis formation, whereas low expression of this growth factor could be involved in delayed wound healing (Eitner et al., 2008; Glim et al., 2013). In line with these results, increased wound healing was observed in diabetic mice when PDGF-CC was applied (Gilbertson et al., 2001). Diabetes mellitus is one of the leading causes of impaired wound healing. A study on diabetic rats dem-onstrates that a certain expression level of PDGF is necessary for normal tissue repair (Li et al., 2008).
4.3. Cardiac remodeling
PDGF-D is also suggested to be involved in cardiac remodeling and cardiac repair in infarcted hearts of rats. All PDGF ligands and receptors were expressed in normal myocardium. After cardiac infarction, increased expression of PDGF-D had been significantly induced in the infarcted myocardium and was primarily expressed by endothelial cells, macrophages and myofibroblasts, whereas expression of PDGF-B and PDGF-C were reduced (Zhao et al., 2011). In another study, PDGF-D induced cardiac remodeling in a mouse model where PDGF-D was overexpressed, specifically in the heart. Overexpression of PDGF-D caused cardiacfibrosis followed by dilated cardiomyopathy, proliferation of interstitialfibroblasts, extensive deposition of collagen, vessel dilation, locally decreased capillary density, and an increased number of SMC-coated vessels (Ponten et al., 2005). Overexpression of PDGF-C in heart-specific transgenic mice also induced a less developed cardiac fibrosis with hyperplasia offibroblast-like cells and dilated cardiomyopathy (Ponten et al., 2003). The influence of PDGFs in cardiac allograft rejection was shown in studies by Tuuminen and colleagues showing that they all, with the exception of PDGF-B, increased
TGF-b
1 chronic rejection in rat cardiac allografts (Tuuminen et al., 2006, 2009). Intracoronary adeno-associated virus-mediated PDGF-C and PDGF-D transfer augmented cardiac allograft inflammation, fibrosis and chronic rejection. Based on these results, there is a potential that inhibition of PDGF-A, -C and -D signaling may inhibit chronicrejection of cardiac allografts.
Fan and colleagues investigated regulation of PDGF signaling pathway in myocardial fibrosis using desoxycorticosterone-induced hypertensive, salt-sensitive rats (Fan et al., 2013). Expres-sion of all members of the PDGF family increased, with the exception of PDGF-D, which remained unchanged. Use of the anti-inflammatory drug fasudil inhibited myocardial inflammation and expression of PDGF-A and PDGF-B. PDGF-C and PDGFR-
a
were reduced whereas PDGFR-b
was unchanged.4.4. Adipocyte metabolism and angiogenesis
Interestingly, results by Seki and colleagues suggest that angiogenic endothelial cells may modulate adipocyte metabolism and may provide a new target for treatment of obesity and meta-bolic disease (Seki et al., 2016). Endothelial production of PDGF-C during white adipose tissue angiogenesis regulated browning of the fat. Further, deletion of endothelial knockout of the Pdgf-c gene or usage of PDGFR-
a
neutralizing antibodies impaired conversion of white fat to beige fat.4.5. Neovascularization in ischemia
The formation of collaterals and neovascularization to maintain blood circulation in ischemic vessels is important for maintaining normal function but may also be a disadvantage in cases of tumorigenesis.
In cell culture, several types of vascular endothelial cells are able to express PDGFR-
a
and PDGFR-b
(Lee et al., 2013; Marx et al., 1994; Plate et al., 1992; Smits et al., 1989). The in vitrofinding of functional PDGFR on human microvascular endothelial cells suggests a direct role of PDGFs in endothelial cells and SMCs and the importance of PDGF in neovascularization (Beitz et al., 1992; Marx et al., 1994; Risau et al., 1992; Smits et al., 1989). However, whether PDGF signaling has a direct effect on endothelial cells in vivo is still Fig. 2. Schematicfigure describing expression and role of PDGF-C and PDGF-D in vascular wall in vivo. PDGF-C and PDGF-D are produced by endothelial cells and SMCs and promotes migration and proliferation primarily of SMC in vivo and activation of MMPs as well as activation offibroblasts.unclear. Further, PDGFR-
a
and PDGFR-b
were found to be expressed on newly formed blood vessels (Cao et al., 2002).Li and others have reported direct effects of PDGF-CC on endo-thelial cells or their progenitor cells in in vitro studies (Gilbertson et al., 2001; Li et al., 2005). Endothelial progenitor cells partici-pate in the neovascularization and re-endothelialization process that follows vascular injury. Endothelial progenitor cells’ role in vascular injury repair involves an interaction with platelets, which are involved in the recruitment of endothelial progenitor cells to sites of vascular injury. PDGF-C is able to stimulate the endothelial progenitor cells recruitment from bone marrow and promote their differentiation (Dimmeler, 2005; Li et al., 2005), suggesting that PDGF-C stimulates angiogenesis by affecting endothelial cells. There is further evidence that PDGF-C and PDGF-D contribute to angiogenesis (Li and Eriksson, 2003; Li et al., 2005; Ustach et al., 2004). PDGF-C also induced angiogenesis in chicken embryos and mouse corneas (Cao et al., 2002). In addition, administration of PDGF-C has been found to promote post-ischemic revascularization of mouse hearts and hind limbs (Li et al., 2005). Recently it was reported that dysregulation of PDGF-C expression in limb tissues of diabetic mice contributed to impaired angiogenesis and that PDGF-C might be a novel target for the treatment of ischemic cardiovas-cular diseases in diabetes (Moriya et al., 2014).
PDGF-C acts on the PDGFR-
a
, which is upregulated in vessels in ischemic hearts and it thus stimulates the migration of endothelial cells and SMCs (Dimmeler, 2005). Indirect evidence that PDGF-C contributes to angiogenesis was shown by high levels of PDGF-C in angiogenic tissues, such as tumors, placenta, ovary and embry-onic tissues, suggesting that PDGF-C induces growth of new blood vessels (Cao et al., 2002; Clara et al., 2014). Furthermore, PDGF-C was demonstrated to be a novel potent pro-angiogenic factor that induces endothelial cells proliferation in the kidney (Boor et al., 2010).In 2007 Wang and colleagues showed that downregulation of PDGF-D led to the inactivation of Notch-1 and NF-kappaB DNA-binding activity, which resulted in downregulation of target genes such as VEGF and the activity of MMP-9 (Wang et al., 2007). Their results also showed that the medium from downregulated PDGF-D inhibited tube formation of human umbilical vascular endothelial cells. This is in agreement with results from Zhao et al. that showed that silencing of PDGF-D also resulted in the reduction of VEGF in gastric cancer cells (Zhao et al., 2010).
4.6. Neovascularization in tumors
Uncontrolled blood vessel growth from existing blood vessel tissue, which is one of the important mechanism activated in cancer, involves a large spectrum of signaling molecules as well as vascular cells, stromal fibroblasts and inflammatory cells (Cao, 2013; Manzat Saplacan et al., 2017). These cells are constantly exposed to growth factors and cytokines, which modulate tumor growth, invasiveness and metastasis (Hanahan and Weinberg, 2011). PDGFs and their receptors play a critical role for angiogen-esis because they are often expressed in diverse tumors, which correlates with tumor growth and invasion (Cao, 2013). The critical role for PDGF-C is its expression and upregulation in tumor endo-thelial cells (Clara et al., 2014; Crawford et al., 2009), where it most likely promote angiogenesis by activation of PDGFR-
aa
andPDGFR-ab
in endothelial cells (Cao et al., 2002). Conversely, reduction or blocking of tumor angiogenesis and growth was found by inhibiting PDGF-C (Crawford et al., 2009; Hou et al., 2010). In a melanoma model, tumor-derived PDGF-C recruitedfibroblasts and promoted tumor growth and angiogenesis (Anderberg et al., 2009). An interestingfinding is that overexpression of PDGF-D increases drug delivery of the chemotherapy drug doxorubicin in mice bynormalizing blood vessels in tumors and thereby improves the efficacy of chemotherapy (Liu et al., 2011).
4.7. Single nucleotide polymorphisms
PDGF-C and PDGF-D have several potential synonymous and non-synonymous single nucleotide polymorphisms (SNPs). In an early attempt to identify novel SNPs in cardiovascular disease, Peden et al. found several new loci (Coronary Artery Disease Genetics, 2011). One of the hits belonged to rs974849 and was thought to belong to the PDGF-D gene. Further, Zhou and col-leagues evaluated the results from Peden et al. in Europeans and in South Asians in the Han Chinese population (Zhou et al., 2012). Although they included only 161 patients with coronary heart disease and 112 controls, they could determine that SNP rs974849 was associated with an increased risk of coronary heart disease. This SNP has also been associated with increased cardiovascular mortality in elderly males (Alehagen et al., 2016). However, recent data reveals that this SNP is located about 120 Kb away from the PDGF-D gene and is actually much closer to a microRNA in an area of long intergenic noncoding RNAs.
Another SNP more close to the PDGF-D gene, 858A/C, rs3809021, was studied in patients with stroke, and the AA geno-type was associated with increased risk for non-hypertensive intracerebral hemorrhage (Bai et al., 2012). Not far from this SNP, in the first intron at position þ3166, rs7950273 was studied in ischemic stroke but no significant differences were found (Han et al., 2016). However, the study found an association between the SNP and ischemic stroke in subjects without a history or family history of hypertension or diabetes in a Chinese population.
Current studies indicate that abnormal PDGF-D activity could be causative in cardiovascular disease, emphasizing the importance of PDGF-D in these conditions. However, the review of the literature revealed that not many studies have been done on genetic varia-tions of PDGF-C and PDGF-D in vascular disease.
5. Animal models to study the role for PDGF-C and PDGF-D in vascular diseases
Diseases involving cardiac and vascular complications are often complex and studying the molecular mechanisms controlling these diseases is a challenge. However, the development of different animal models of vascular and cardiovascular diseases has provided us with important tools for investigating the pathophysiology of different diseases and evaluating new therapeutic strategies. Further, the ability to generate knockout mice has made it possible to understand the in vivo function(s) of different genes and spe-cifically studying the lack of gene of interested in disease situations. In addition, the use of mouse models, where genetic gain-of-function and loss-of-gain-of-function mutations are introduced, are also well established approaches to test the role of certain genes in different pathological conditions such as different vascular dis-eases. PDGF-C and PDGF-D have been studied in relation to vascular and cardiovascular disease by using several different mouse models.
5.1. Knockout mice
Genetic deletions of PDGF-C and PDGF-D have been reported. However, the phenotype of PDGF-C is complicated and background dependent; Pdgfc/mice on a 129S1/Sv genetic background die perinatally from feeding and respiratory problems due to cleft palates. However, Pdgfc/mice on a C57BL/6 genetic background survive, but display cerebral ventricular malformations, abnormal vascularization and skeletal deformations (Ding et al., 2004;
Fredriksson et al., 2012). The first article describing a PDGF-D knockout mouse was recently published and, it showed that in contrast to the other PDGF knockouts, the Pdgfd/is viable, fertile and show no gross abnormalities (Gladh et al., 2016). The pheno-type of the PDGF-C deficient mouse makes it less suitable for use in vascular disease models while the PDGF-D deficient mouse is much more useful in different pathological models.
Although a severe phenotype was reported in the PDGF-C knockout mice it have been used to evaluate the effect of PDGF-C activity in a neurodegenerative vascular disease such as amyo-trophic lateral sclerosis where the SOD1G93A strain was crossed with Pdgfc/ mice (SOD1G93APdgfc/). Decrease of Pdgfc expression restored vascular barrier properties, reduced motor neuron loss and delayed symptom onset (Lewandowski et al., 2016).
In addition, Pdgfc/mice has also been used in several other pathological mouse models to assess role of PDGF-C. Since PDGF-C has been suggested to have an important role in kidneyfibrosis, PDGF-C deficiency has been investigated in several different mouse models (unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion (I/R) and Col4a3-deficient (Alport) mice) of renal fibrosis. In the UUO model it was demonstrated that lack of PDGF-C reduced the development of renalfibrosis as well as decreased the leukocyte infiltration. Yet, lack of PDGF-C did not have any effect on microvascular function and tissue perfusion when assessed as capillary rarefaction it the three different kidneyfibrosis models mentioned above (Boor et al., 2015; Eitner et al., 2008).
Lately, the role of PDGF-C in adipocyte metabolism was inves-tigated in a mouse model where PDGF-C deficient mice was treated with a
b
3-adregenic agonist to induce adipose angiogenesis and browning of subcutaneous white adipose tissue. In this study it is suggested that lack of PDGF-C impairs browning of white adipose tissue (Seki et al., 2016).Although the PDGF-D knockout mouse was recently reported, genetic deletion of pdgfd have been described in two distinct models of renal fibrosis UUO and I/R. Pdgfd/ mice showed significantly reduced renal interstitial fibrosis in both models of renal scarring (Buhl et al., 2016). Furthermore, disruption of PDGF-D signaling in the RIP1-TAg2 mouse model of pancreatic neuro-endocrine tumors delayed tumor growth and prolonged survival without any effects on the vasculature (Cortez et al., 2016).
Atherosclerotic mouse models such as low-density lipoprotein receptor-deficient mice (LDLR/mice) and apolipoprotein E-de fi-cient mice (apoE/mice) are widely used in studying the devel-opment and progression of atherosclerotic lesions. These models are useful tools in determine the role of different genes in athero-sclerotic development as well as they are also versatile for evalu-ating the effectiveness of drugs for treevalu-ating atherosclerosis (Whitman, 2004; Zadelaar et al., 2007; Zaragoza et al., 2011). Still, descriptions of PDGF-C or PDGF-D deficient mice crossed with any of these mice models are lacking. However, upregulation of PDGF-D expression in apoE deficient mice have been described (Ponten et al., 2005).
5.2. Transgenic mice
Transgenic overexpression of PDGF-C and PDGF-D in mice has been described in several different models. Generally, both PDGF-C and PDGF-D inducesfibrosis when overexpressed.
Focusing in particular on mouse models of vascular and car-diovascular diseases, PDGF-C and PDGF-D has been transgenic overexpressed, specifically in the heart using the
a
-myosin heavy chain promoter (Ponten et al., 2003, 2005). Both growth factors induced cardiacfibrosis, which is commonly seen in several car-diovascular complications. Furthermore, several vascularcomplications such as vascular remodeling, including dilation of vessels, increased density of SMC-coated vessels, and proliferation of vascular SMCs, leading to a thickening of tunica media was seen when PDGF-D was overexpressed. Similar vascular abnormalities were seen overexpressing PDGF-C but the thickening of arterial walls was a unique feature induced by PDGF-D overexpression.
In another transgenic mouse model where PDGF-D was over-expressed in the basal epidermal keratinocytes using the K14 promoter, PDGF-D transgenic mice displayed vascular impact such as increased numbers of macrophages and elevated interstitialfluid pressure in the dermis (Uutela et al., 2004).
5.3. Other animal models
Several animal models of AAA are available and they have pro-vided insights into the mechanisms of human AAAs. One commonly used model is infusion of angiotensin II into a hyper-lipidemic mouse such as apoE/mice, where angiotensin II pro-duces large suprarenal AAAs (Zaragoza et al., 2011). Dysregulation of PDGF-D in the form of decreased PDGF-D expression is found in this model (Vorkapic et al., 2016)
Mice are the most commonly used animal model to study different pathological conditions but due to their small size some procedures may be difficult to perform. Rat models are often used to study heart failure because they are larger than mice, which greatly facilitate surgical and postsurgical procedures. Myocardial damage in rat hearts can be induced by several different methods but the most common consists of ligation of the left coronary artery (Zaragoza et al., 2011). Through the use of this method, decreased expression of PDGF-C and increased expression of PDGF-D was found in the infarcted myocardium (Zhao et al., 2011).
6. Proteolytic activation of PDGF-C and PDGF-D
Proteolytic activation is an important regulatory step for many proteins. Proteases often play key roles in many signal transduction pathways by regulating and controlling the levels of critical com-ponents that signals through the pathway. Therefore the amount of protease available can be an important aspect in many pathological conditions. The PDGFs are all proteolytically processed to become mature and active. The classical PDGF-A and PDGF-B chains un-dergo intracellular proteolytic activation, while C and PDGF-D chains undergo extracellular activation to generate active pro-teins. It has been reported that plasmin is able to activate both PDGF-C and PDGF-D. However, due to the wide substrate specificity of plasmin it is probably not the physiologically relevant protease (Fredriksson et al., 2004, 2005; Reigstad et al., 2005). More specific extracellular cleavage of PDGF-C and PDGF-D is performed by serine proteases, tPA activates PDGF-C, while PDGF-D is cleaved by uPA and matriptase (Ehnman et al., 2009; Fredriksson et al., 2004; Reigstad et al., 2005; Ustach et al., 2010; Ustach and Kim, 2005). However, there might be other proteases capable of cleaving PDGF-C and PDGF-D that are still unknown.
The fact that PDGF-C and PDGF-D are secreted as inactive pro-teins that dependend on the availability of the correct proteases complicates the biology and the investigations of their signaling outcomes.
7. Future perspectives 7.1. Pathological conditions
Several of the suggested functions of the novel PDGFs in different pathological vascular conditions come from studies reporting dysregulation of PDGF-C and PDGF-D where they are
either up or down regulated. It might be that PDGF-C and PDGF-D do not need to be overexpressed to cause undesired cellular acti-vation and pathological conditions. If the protease that can activate PDGF-C or PDGF-D is presented in an excess amount, it can cause increased activation of PDGF-C or PDGF-D, without any need for increased expression of the ligand itself. In order to accurately understand the role novel PDGFs play in different vascular patho-logical conditions, it is important to further study the endogenous factors involved in their regulation. The following description of the suggested role of PDGF-C in stroke illustrates why it is so important to understand the exact role of all the players involved in the biology of the novel PDGFs. The serine protease tPA, which is known to dissolve blood clots and to be involved in the activation of PDGF-C, is used to treat ischemic stroke patients. Thus, while tPA helps to dissolve the clot quickly and restore bloodflow to the brain tissue it can also activate PDGF-C that is expressed in the brain, which enhances the opening of the blood-brain barrier. This allows an influx of inflammatory cells into the brain, contributing to edema, hemorrhagic transformation, and increased mortality. Treatment with tPA is the only FDA-approved treatment for stroke, but because of the effects caused by the opening of the blood-brain barrier, it must be started within 4.5 h of symptom onset. This limits the number of patients that can be treated with tPA. However, in animal studies, Su et al. found that blocking PDGFR signaling with imatinib reduced the neurotoxic effects of tPA and allowed later application of tPA after onset of stroke (Su et al., 2009). Further-more, in the recent I-Stroke study by Wahlgren et al. it was sug-gested that imatinib is safe and generally well tolerated in ischemic stroke patients treated with tPA (Wahlgren et al., 2017). These findings not only enable better treatment of stroke patients, they also show how important it is to understand all the players involved in the biology of the novel PDGFs.
7.2. Cross-talk with NRP1
Moreover, another challenge is to interpret the biological sig-nificance of the crossroad between signaling through PDGFR and other receptor systems. Recently, Muhl et al. found that NRP1 can act as a co-receptor for PDGF-D/PDGFR-
b
signaling (Muhl et al., 2017). In that study, they also showed that PDGF-D can induce NRP1 translocation to endothelial cell junctions independently of PDGFR-b
. This suggests that PDGF-D binding to NRP1 could change the availability of NRP1 for other endothelial signaling pathways, such as VEFG-A-VEGFR-2 signaling. This signaling pathway is highly important in vascular development and maintenance, and has also been found to be involved in different pathological con-ditions. Further investigations of the interplay between PDGF-D and NRP1 will contribute to a better understanding of the patho-logical roles of PDGF-D in clinical conditions, such as cardiovascular disorders. In a recent paper, Ruffini et al. reported that PDGF-C promotes human melanoma aggressiveness through activation of NRP1 (Ruffini et al., 2013). Thus, this article shows that PDGF-C also can interact with NRP1. However, more investigation is needed to clarify what role NRP1/PDGF-C interaction plays in various vascular disease diseases.7.3. Other complications
Investigations of the role of naturally occurring PDGF receptor inhibitors in vascular disease has been studied in experimental models of restenosis and atherosclerosis (Ricci and Ferri, 2015). Further detailed studies in other vascular diseases and in ran-domized clinical studies would be of interest. The inhibition role of PDGF-C and PDGF-D in specific signaling pathways needs to be examined.
Another important aspect of PDGF-C and PDGF-D signaling is in the role of adipogenesis and thermogenesis, and especially in regulation of or by perivascular adipose tissue, which has received more attention recently. Here, the involvement of the anti-inflammatory pathway of peroxisome proliferator activator re-ceptors is of interest (Gabrielson et al., 2016).
Finally, genetic variations within the PDGF-C and PDGF-D genes and their implications for vascular disease as well as their regula-tion by microRNAs is still relatively unstudied and so needs further investigation.
Acknowledgements
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Appendix A. Supplementary data
Supplementary data related to this article can be found at
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