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  • 1 Department of Pulmonology, Semmelweis University, Budapest, Hungary
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Abstract

Pulmonary arterial hypertension (PAH) is a rare and progressive disease, characterized by increased vascular resistance leading to right ventricle (RV) failure. The extent of right ventricular dysfunction crucially influences disease prognosis; however, currently no therapies have specific cardioprotective effects. Besides discussing the pathophysiology of right ventricular adaptation in PAH, this review focuses on the roles of growth factors (GFs) in disease pathomechanism. We also summarize the involvement of GFs in the preservation of cardiomyocyte function, to evaluate their potential as cardioprotective biomarkers and novel therapeutic targets in PAH.

Abstract

Pulmonary arterial hypertension (PAH) is a rare and progressive disease, characterized by increased vascular resistance leading to right ventricle (RV) failure. The extent of right ventricular dysfunction crucially influences disease prognosis; however, currently no therapies have specific cardioprotective effects. Besides discussing the pathophysiology of right ventricular adaptation in PAH, this review focuses on the roles of growth factors (GFs) in disease pathomechanism. We also summarize the involvement of GFs in the preservation of cardiomyocyte function, to evaluate their potential as cardioprotective biomarkers and novel therapeutic targets in PAH.

Introduction

Pulmonary hypertension (PH) is a progressive disease characterized by an increased mean pulmonary arterial pressure (mPAP ≥25 mmHg) [1]. Classes of PH are defined and regularly updated by the WHO based on hemodynamic and clinical characteristics (Table 1). According to the hemodynamic definition pre-capillary and post-capillary PH can be distinguished by a normal and elevated pulmonary arterial wedge pressure (PAWP), respectively. The predominant pathophysiological abnormality in pre-capillary PH is the remodeling of the arterial wall, particularly in pulmonary arterial hypertension (PAH, WHO group 1). The increased proliferation and inhibited apoptosis of lung vascular endothelial cells, pulmonary arterial smooth muscle cells (PASMC) and fibroblasts result in remodeling of the muscular type of pulmonary arteries, manifested as intimal hyperplasia, medial thickness, plexiform lesions and in situ thrombosis [1]. In addition, other mechanisms as hypoxic vasoconstriction (WHO group 3) and mechanical obstruction by thrombi (WHO group 4) also play a role in the increase in pulmonary vascular resistance (PVR). In post-capillary PH the underlying disorder is a left heart disease and the consequent pulmonary congestion causes a rise in PAWP (WHO group 2). In combined pre-capillary and post-capillary PH in addition to the presence of increased left ventricle (LV) pressure and PAWP, pulmonary arterial remodeling is pronounced and leads to an increase in PVR. Irrespective of the etiology of PH right ventricle (RV) pressure overload leads to right ventricular myocardial hypertrophy, dilatation and right ventricular failure at advanced stages. The mechanism of RV adaptation involves complex processes, which are influenced by different factors including the etiology of PAH, genetic predispositions, neurohumoral regulation, immune and inflammatory activation [2].

Table 1.

Classification of pulmonary hypertension

Hemodynamic classificationPulmonary hypertension mPAP >25 mmHg
Pre-capillary PH, PAWP <15 mmHgPost-capillary PH, PAWP >15 mmHg
Clinical classificationWHO Group 1. Pulmonary arterial hypertensionWHO Group 2. PH due to left heart disease
WHO Group 3. PH due to lung disease and/or hypoxia
WHO Group 4. Chronic thromboembolic PH or other pulmonary artery obstructions
WHO Group 5. PH with unclear and/or multifactorial mechanisms

mPAP: mean pulmonary arterial pressure; PH: pulmonary hypertension; PAWP: pulmonary arterial wedge pressure.

Growth factors (GFs) are diffusible signaling proteins that stimulate cell growth, cellular differentiation and survival, tissue inflammation and tissue repair. Several studies described the involvement of GFs in the development of PAH [3–6]. Moreover, accumulating evidence suggests that they may also contribute to the preservation of right heart function, but also influence the development of RV remodeling and disease progression (Fig. 1). Notably, some of these mediators also have well-known effects during myocardial protection in cardiac disorders such as ischemic heart disease, myocardial hypertrophy or left heart failure [3, 4]. GFs may, in addition, support better myocardial adaptation in response to pressure overload of the RV and may be related to better prognosis in PAH. In the current review, we aim to systematically discuss the evidence on the involvement of the major GFs in the pathophysiology of PAH and the consequent right heart failure and evaluate their potential as cardioprotective biomarkers.

Fig. 1.
Fig. 1.

The roles of growth factors in the pathophysiology of PAH. Growth factors are produced in pulmonary vascular cells and cardiomyocytes in response to various stimuli in PAH. These factors play a role both in the development of pulmonary vascular remodeling and the modulation of right ventricular function. FGF: fibroblast growth factor, IGF-I: Insulin-like growth factor-I; PAH: pulmonary arterial hypertension; RV: right ventricle; TGF-β:transforming growth factor-β; VEGF: vascular endothelial growth factor

Citation: Physiology International Acta Physiol Hung 107, 2; 10.1556/2060.2020.00021

The regulation of growth factors (GFs) during the development of PAH

GFs regulate various cellular functions such as survival, proliferation, migration and differentiation and thus play significant roles in the repair mechanisms of organs under physiological circumstances [3].

In PAH GFs affect the development of vascular remodeling, the proliferation of endothelial cells, smooth muscle cells and fibroblasts, and the formation of the plexiform lesions [5, 6]. Several GFs are expressed locally in the pulmonary parenchyma and in the plexiform lesions. The expression of platelet-derived growth factor (PDGF) and PDGF receptor was elevated in explanted lungs of patients with severe PAH [6], and the appearance of vascular endothelial growth factor (VEGF) and VEGF receptors is confirmed in the plexiform lesions and medial smooth muscle cells of the proximal arteries during lung autopsies [7]. Nerve growth factor (NGF) expression and its secretion were increased in the pulmonary arteries of patients with pre-capillary PH complicating chronic obstructive pulmonary disease (group 3 in Table 1) and in experimental PAH induced by monocrotaline administration or chronic hypoxia [8]. Other studies proved elevated circulating levels of these factors in patients, and found high transpulmonary gradients of these molecules suggesting their pulmonary production [9].

The mechanisms behind the abnormal expression of GFs in the lungs in PAH are only partially known, and multiple pathways have been implicated. In 80% of familiar PAH (FPAH) the mutations of the bone morphogenic protein receptor type 2 (BMPR2), a member of the transforming growth factor-β (TGF-β) superfamily can be identified, and approximately 20% of sporadic idiopathic PAH (IPAH) patients carry this mutation. Epigenetic factors play a role in its penetrance [10]. BMPs can activate various receptors such as the BMP type I and type II and also the activin type II receptor, however only BMPRII is specific for BMPs. In the vasculature the signaling is mainly mediated by BMP2, 4, 6, 9, and 10, which can activate all three receptors and play a prominent role in vasculogenesis and angiogenesis. The disturbed BMP signaling via the intracellular specific intracellular signal transduction protein (SMAD) pathway contributes to the development of abnormal vascular remodeling in PAH [11].

A further 5% of FPAH patients have rare mutations in other genes of the TGF-β superfamily including activin-like receptor kinase-1 or endoglin. These genetic disorders result in abnormal tissue repair and vascular remodeling caused by the abnormal growth response of pulmonary artery smooth muscle cells and the reduced apoptosis of endothelial cells [12]. Interestingly, in the animal model of Schistosoma infection, PAH is induced as a result of the pulmonary activation of TGF-β by bone marrow-derived thombospondin-1 [13].

Hypoxia is a powerful stimulus for pulmonary vasoconstriction and pulmonary vascular remodeling. The expression of VEGF and FGF (fibroblast growth factor)-2 is increased in endothelial cells by hypoxia-induced signaling molecules [14, 15]. Furthermore, the expression of the growth differentiation factor 11, a member of the BMP/TGF-β superfamily, is induced in pulmonary artery endothelial cells under hypoxia, which plays a crucial role in the development of hypoxia-induced PAH in animal models [16].

Exogenic stimuli such as drugs and toxins have been shown to be involved in the development of PAH. The tyrosine kinase inhibitor (TKI) dasatinib is successfully used in the treatment of chronic myelogenous leukemia, but case reports found an increased prevalence of PAH in treated patients, where PAH was (at least partly) reversible in most cases after the cessation of therapy [17, 18]. It is presumed that the modulation of PDGF signaling by TKIs is responsible for the development of PAH [19].

The adaptation of the right ventricle (RV) in PAH

The anatomy and function of the RV is partially distinct from the LV, which is also reflected in its different adaptation mechanisms in response to pathophysiological processes. The RV pumps the blood into the low vascular resistant pulmonary circulation, a process requiring less stroke work compared to that of the LV, but the stroke volume is similar [20]. Exercise results in a decrease in PVR to prevent a significant increase in pulmonary pressure. Consequently, under physiological circumstances, the RV wall contains less muscular tissue and its compliance is also greater than observed in the LV. Therefore, in contrast to the LV, the RV can undergo significantly higher volume changes under pathological conditions [21].

In PAH, sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling cause elevated PVR which is resistant to physical exercise. Due to the gradually increasing PVR, the RV produces higher systolic pressures to maintain blood flow. The constantly elevated RV and pulmonary pressures result in right ventricular remodeling. In early disease stages, concentric myocardial hypertrophy of the right ventricular wall is observed (adaptive remodeling), which is the result of upregulated intracellular protein synthesis and the increased size of cardiomyocytes; therefore, ventricular contractility and the systolic function also improve. As a consequence, hemodynamic parameters such as cardiac index and right atrial pressure remain normal [22].

As the disease progresses, the gradually increasing pressure overload induces eccentric myocardial hypertrophy mainly in the free wall of the RV, which is associated with increased collagen production but also with excessive degradation of normal extracellular matrix in the myocardium (maladaptive remodeling). The maladaptive hypertrophy and the additional volume overload due to increasing functional tricuspid regurgitation lead to progressive dilatation of the RV, deterioration of contractility and the systolic function [23]. This mechanism results in progressive RV dysfunction and failure at advanced disease stages as summarized in Fig. 2.

Fig. 2.
Fig. 2.

The effects of increased pulmonary vascular resistance on the right ventricle in PAH. A schematic presentation of the vicious circle induced by increased pulmonary arterial vascular resistance on the morphology and function of the right ventricle in PAH. Mechanisms potentially influenced by growth factors are highlighted in italics. RV: right ventricle

Citation: Physiology International Acta Physiol Hung 107, 2; 10.1556/2060.2020.00021

The prognosis of PAH is strongly associated with the grade of structural abnormalities of the RV [24]. More specifically, the increased right ventricular diameter is a biomarker of a poor prognosis; however, the increased wall thickness is related to reduced risk of mortality in patients with dilated RV [25]. In line with this, increasing evidence suggests that the detailed assessment of RV structure and function holds relevant prognostic information and can support treatment decisions to improve clinical outcomes [26].

The molecular mechanisms of RV myocardial adaptation are not yet completely understood. In PAH the pressure overload induces wall stretch, being the main trigger to initiate myocardial adaptation, which improves RV systolic function during early stages. Subsequently, in further phases of PAH ischemia and oxidative stress in the myocardium activate neurohumoral, inflammatory and immune processes, leading to extracellular matrix degradation and cardiomyocyte dysfunction and/or apoptosis [2]. These processes induce chamber dilatation and systolic dysfunction. The peculiarity of the right ventricular muscle is that when PVR is normalized (e.g. after pulmonary endarterectomy or lung transplantation), size, wall thickness and molecular differences normalize very rapidly through reversible remodeling [24].

As described above, GFs contribute to the development of vascular remodeling in PAH, but some could also have a role in controlling myocardial adaptation to PAH. Myocardial ischemia, the imbalance between myocardial oxygen supply and oxygen demand, is caused by several mechanisms in PAH [27]. The disturbance of the alveolar gas exchange leads to chronic systemic hypoxemia. On the one hand, the increased right ventricular wall tension associated with systemic hypotension impairs coronary perfusion. On the other hand, myocardial hypertrophy and the increased wall tension require increased oxygen supply. Several GFs are released by the myocardium during myocardial ischemia including the angiogenetic GFs such as VEGF, FGF and others which have direct myocardial protective effect such as IGF and TGF-β [3, 4].

In the following sections, we discuss GFs which potentially exert cardioprotective effects, contribute to right ventricular adaptation, as well as to hemodynamic changes in PAH. The known intracellular pathways of these factors are shown in Table 2 and Fig. 3.

Table 2.

The intracellular signaling pathways of growth factors with putative cardioprotective effects

MediatorReceptor subtypesIntracellular pathwayEffectsReferences
VEGFVEGFR1MEK1/2 p90rskactivation of cardiac myocytes and fibroblasts in response to ischemic stresses[28]
VEGFR2
VEGFR2PI3K-Akt-eNOSendothelial cell survival[29, 30]
vascular neogenesis in the myocardium
VEGFR2ICPP-induced ERK phosphorylationimprovement of ischemia-reperfusion-induced mitochondrial dysfunction[31]
TGF-βTGF-β RII+RISmad 3infarct healing and cardiac remodeling[7]
TGF-β RII+RIp42/p44 MAPKrelieving apoptosis of myocytes and limiting infarct size[32]
TGF-β RII+RIMAPKprotecting against myocardial ischemia-reperfusion injury by attenuating inflammation and cardiomyocyte apoptosis[33]
FGF1, FGF2FGFR1PI3K-Akt MEK1/2-Erk 1/2direct cardioprotective effect[3]
FGF2FGFR1PI3K/Aktprotecting cardiomyocytes against oxidative stress[34]
FGFR1MAPKpromoting cardiac hypertrophy and fibrosis[35]
FGF21FGFR1cERK1/2-p38 MAPK-AMPKpreventing cardiomyocyte apoptosis[36]
IGF-IIGF-IRPI3K/Akthypertrophy and proliferation of cardiomyocytes[37, 38]
adaptive right ventricular hypertrophy
PDGF-BBnot investigatedPI3K/Aktpromoting contractility[39]
preventing apoptosis of cardiomyocytes
PDGF-BBPDGFR-βERK1/2, MEK, PLC, PKCpromoting growth of cardiomyocytes[40]

Akt: protein kinase B; AMPK: AMP-activated protein kinase; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal regulated kinase; FGF: fibroblast growth factor, FGFR: FGF receptor; ICPP: increasing capillary permeability protein; MEK or MAPK: mitogen-activated protein kinase, p90rsk – ribosomal s6 kinase; PI3K: phosphoinositide 3-kinase; PDGF: platelet-derived growth factor; PKC: protein kinase C; PLC: phospholipase C; TGF-β: transforming growth factor beta; TGF-β R: TGF-β receptor; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor.

Fig. 3.
Fig. 3.

Intracellular pathways of growth factors involved in myocardial protection in PAH. Growth factors use similar intracellular pathways in adaptation mechanisms of cardiomyocytes. These mechanisms support myocardial viability against ischemic and metabolic injury, might aid the development of adaptive myocardial hypertension and could lead to the preservation of the right ventricle function in early stage of PAH. VEGFR: vascular endothelial growth factor receptor; TGFβ1R: transforming growth factor-β1 receptor; FGFR: fibroblast growth factor receptor; IGF-IR: Insulin-like growth factor-I receptor; PDGFR: Platelet-derived growth factor receptor; Ras: intracellular signal transduction protein; MEK or MAPK: mitogen-activated protein kinase; SMAD: specific intracellular signal transduction protein; ERK: extracellular signal regulated kinase; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B

Citation: Physiology International Acta Physiol Hung 107, 2; 10.1556/2060.2020.00021

Vascular endothelial growth factor (VEGF)

Members of the VEGF family including VEGF-A (called generally VEGF), -B, -C, -D, -E and the placental GFs play significant roles in angiogenesis [41]. VEGF-A is the most potent angiogenic factor, and it is produced in high amounts in the adult lung. The tyrosine kinase VEGF receptors are VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (FLT-4). VEGFR-1 and VEGFR-2 are expressed in vascular endothelial cells, and upon activation they induce signals for proliferation, migration and remodeling.

VEGF was suggested to be involved in the formation of plexiform lesions, as this cytokine, produced by the modified smooth muscle cells of the plexiform lesions and the medial smooth muscle cells, can activate pulmonary endothelial cells expressing the VEGF receptor [42]. However, the overexpression of VEGF-A or VEGF-B in the lungs can partially restore endothelium-dependent function and ameliorate PAH in an animal model of chronic hypoxia [43, 44]. In support, VEGFR-2 blockade in combination with chronic hypoxia resulted in the development of severe PAH in an experimental model as the result of precapillary arterial occlusion induced by proliferating endothelial cells [45].

VEGF can be generated in the myocardium in response to myocardial ischemia [46]. VEGFR-1 and VEGFR-2 are expressed on both pulmonary vascular endothelial cells and cardiomyocytes, at least in rat models of PH [30], suggesting that VEGF stimulation can induce acute or chronic cardiac effects either by directly acting on cardiomyocytes or by exerting vascular effects. These receptors activate known cytoprotective pathways in myocytes such as the MEK1/2-Erk1/2-p90rsk [3], which promotes cell survival by increasing the adhesive interactions between cardiomyocytes and extracellular matrix components [47]. In an animal model of hypoxia-induced PH the increased level of VEGF mRNA has been demonstrated in the myocardium, suggesting that VEGF may be one of the factors in the development of hypoxia-induced angiogenesis as shown by an increase in the number of capillaries per myocyte [30]. In support, VEGF mRNA expression was increased in rat RVs with adaptive hypertrophy compared to control animals, but it was unchanged in RV failure [37]. Moreover, the administration of VEGF to the recovery solution of the isolated rat heart can improve the functional recovery of the myocardium after ischemia-reperfusion injury [48].

An increase in circulating VEGF concentration was measured in patients with IPAH compared to controls [49, 50]. In patients there was a significant positive relationship between plasma VEGF concentrations and the tricuspid annular plane systolic excursion, which is an echocardiographic marker of right ventricular systolic function [50]. In other words, patients with better right heart function had higher circulating VEGF values suggesting a possible role for this mediator in protection against the development of right ventricular failure. In line with this, in an experimental model of LV hypertrophy the overexpression of VEGF using a viral vector resulted in the preservation of cardiac function [51]. Interestingly, the plasma VEGF levels of patients did not change after 3 months of PAH-targeted therapy [49], although treatment was associated with a decrease in PVR and an improvement of cardiac index.

The association of circulating GFs level with clinical characteristics in patients with PAH are listed in Table 3.

Table 3.

Plasma growth factor concentration and its association with clinical factors in patients with PAH

Growth factorPatient populationConcentrationAssociation with clinical factorsReference
VEGFIPAH82/0–345/pg/mLTAPSE[50]
primary PH41.4 (7.5–92) pg/mLwhen combined with FGF-2:
  • mean PAP
  • right atrial pressure
  • WHO functional class
[52]
TGF-βIPAH5.02 (3.34–8.29) ng/mL• WHO functional class[53]
hereditary PAH4.36 (2.98–7.05) ng/mL• independent factor for all-cause mortality
FGF2primary PH2.15 (0.5–9.3) pg/mL• WHO functional class[52]

Data are shown as median/range/or (interquartile range). FGF: fibroblast growth factor; IPAH: idiopathic pulmonary arterial hypertension; PAH: pulmonary arterial hypertension; PAP: pulmonary arterial pressure; PH: pulmonary hypertension; TAPSE: tricuspid annular plane systolic excursion; TGF: transforming growth factor; VEGF: vascular endothelial growth factor, WHO: World Health Organization.

Transforming growth factor-β (TGF-β)

TGF-β is a pleiotropic and multifunctional polypeptide, which is a member of the TGF superfamily together with other proteins including activins and BMP. TGF-β binds to the type II TGF-β1 receptor, which activates the TGF-β1 receptor type I, and the signal is transmitted by these transmembrane serine/threonine kinase receptors to activate the Smads and Smad-independent pathways, the phosphoinositide 3-kinase (PI3K)/Akt and the MEK1/2-Erk1/2 kinase cascades [3]. TGF-β regulates many physiological processes such as embryonic development, cell growth and differentiation, immune processes and angiogenesis and it also stimulates the production of extracellular matrix components, the synthesis of elastin, and it can control the proliferation of smooth muscle cells as well [54].

An elegant human study showed that in normal human pulmonary arteries TGF-β receptor expression is more pronounced in endothelial cells than in vascular smooth muscle cells [55]. Plexiform lesions in IPAH are associated with the loss of TGF-β signaling, suggesting a role for this pathway in the abnormal growth of endothelial cells in patients. In contrast, a rare form of PAH associated with schistosomiasis showed heightened TGF-β signaling in the pulmonary arteries both in patients and in infected mice [56]. Importantly, the blockade of TGF-β signaling yielded protection against PAH in the animal model. Furthermore, the upregulation of pulmonary TGF-β signaling was observed in the experimental model of monocrotaline-induced PAH, and the blockage of TGF-β receptor type I resulted in attenuated morphological presentation of pulmonary vascular remodeling including decreased early vascular cell apoptosis, adventitial cell proliferation and matrix metalloproteinase expression [57]. The increased expression of the growth differentiation factor-15 (GDF-15), a distant member of the TGF-β cytokine superfamily was observed in macrophages in the lungs of patients with PAH associated with systemic sclerosis [58]. GDF-15 can exert anti-apoptotic effects on the cells of the pulmonary vasculature and contribute to vascular remodeling.

The function of TGF-β during myocardial repair and remodeling after cardiac injury has been studied in cardiac disorders. TGF-β pre-treatment reduced the myocardial infarct size in an animal model by decreasing the level of oxidative stress markers in the coronary circulation and preserving endothelium-dependent coronary relaxation [59]. Other studies attributed these direct cardioprotective effects of TGF-β to intracellular signal transduction pathways including the MEK1/2-Erk1/2, a component of the RISK pathway [3]. Extensive animal studies on left heart failure showed that TGF-β overexpression promotes myocardial hypertrophy, remodeling and fibrosis (reviewed in detail [60]), suggesting an important role in myocardial adaptation, i.e. the development of ventricular hypertrophy and diastolic dysfunction. Indeed, serum TGF-β levels correlated with left ventricular structural abnormalities in long-term hypertensive patients [61]. An excessive TGF-β production may be harmful to myocardial function by increasing myocardial fibrosis. In support, a highly elevated plasma TGF-β concentration was found to be an independent predictor of all-cause mortality in patients with IPAH and FPAH [53]. Nonetheless, a moderate induction of TGF-β signaling may be necessary for cardiac adaptation during pressure overload, as this GF inhibits uncontrolled matrix degradation that could result in cardiac dilation [60].

Fibroblast growth factor (FGF)

Fibroblast growth factors are multifunctional polypeptides that affect cell growth and differentiation. The FGF family has 23 members, and certain mediators exert intracrine stimulus, while others have paracrine or endocrine effects. The paracrine and the endocrine members bind to tyrosine kinase receptors (FGFR 1-4), which mainly activate the intracellular signal transduction protein-mitogen-activated protein kinase (RAS-MAPK) or PI3K/Akt intracellular pathways to induce mitogenic cell response and promote cell survival [27]. In addition, FGF-2 stimulation inhibits endothelial cell apoptosis by inducing signaling via the pathways of B-cell lymphoma (BCL)2 and BCL extra long [62]. Several members of the FGF family, including FGF-2, -16, -21 and -23 have been implied in the pathophysiological processes of cardiac diseases [35]. Among them, the effects of FGF-2 have been studied most extensively in cardiovascular pathologies.

The upregulated expressions of FGF-2 and FGF receptor 1 (FGFR-1) were demonstrated in the pulmonary arteries of animals with monocrotaline-induced PAH, and FGFR-1 blockage resulted in attenuated vascular remodeling [63]. Additionally, endothelial cells isolated from distal pulmonary arteries of patients with IPAH showed heightened FGF-2 production. Stimulation with FGF-2 resulted in increased proliferative response and survival of these cells, whereas dampened FGF-2 signaling normalized these cellular functions suggesting a role of FGF-2 in the development of an abnormal phenotype of pulmonary arterial endothelial cells [62]. Benisty et al. found that both urinary and plasma FGF-2 were significantly higher in patients with PAH than in control subjects. Interestingly, there was a difference in FGF-2 concentrations according to etiologies of PH, with the highest levels seen in patients with primary PAH compared to patients with congenital heart disease or connective tissue disease. However, they did not find a relationship between either blood or urinary FGF-2 levels and cardiac index, suggesting that an increase in mediator concentrations was not the result of a low cardiac output state or systemic hypoperfusion [52].

FGF-2 is released from damaged myocardial cells and it is mainly stored in the extracellular matrix. It modulates vascular endothelial and smooth muscle cell growth and migration, and the synthesis of extracellular matrix proteins. Accordingly, FGF-2 can stimulate the development of ventricular hypertrophy and fibrosis during cardiac remodeling by activating the MAPK signal pathway [35]. It was demonstrated in an in vitro model that isolated adult myocytes upregulated protein synthesis and increased in size in response to co-culture with FGF-2 [64]. In line with this, FGF-2-deficient mice showed a failure in the development of cardiac hypertrophy when exposed to pressure overload to the LV [65]. Furthermore, FGF-2 overexpression led to excessive hypertrophic response to isoproterenol, which was associated with ischemic preconditioning and the increased resistance of the myocardium to ischemia-reperfusion injury [66]. Hence, FGF-2, secreted by cardiomyocytes in response to myocardial damage such as ischemia, can play a role in myocardial protection and regeneration processes [67]. Accordingly, pre-treatment with FGF-2 reduced the size of the infarcted area in the isolated rat heart [68]. Other authors demonstrated that FGF-2 given during reperfusion protected against ischemia-reperfusion injury of the ex vivo heart [69].

Insulin-like growth factor-I (IGF-I)

IGF-I is a polypeptide produced in the liver as a result of growth hormone stimulation, but a limited amount can also be synthetized in the target tissue including the heart. It is bound to IGF-binding factors in the circulation, and only a small fraction of IGF-I (approximately 1%) can be found as a free molecule [70]. This factor exerts its biological actions by binding to the IGF-I receptor (IGF-IR), a tyrosine kinase receptor, which is expressed in multiple tissues, and upon activation it supports cell survival, stimulates cellular migration and proliferation, and suppresses autophagy via multiple intracellular cascades including PI3K/Akt, ERK, Ras/Raf/mitogen-activated protein kinase pathways [3]. IGF-I promotes the synthesis and inhibits the breakdown of proteins in cardiomyocytes via the PI3K/Akt cascade, thereby contributing to physiological cardiac hypertrophy [38, 71].

IGF-I was implicated in the development of pulmonary vascular remodeling. The proliferation of PASMC was attenuated in the absence of IGF-I or after the inhibition of IGF-IR. In addition, the smooth muscle cell-specific deletion of IGF-I inhibited the development of hypoxia-induced PH in neonatal but not adult mice [72].

Early studies showed that IGF-I treatment attenuates hypoxia-reoxygenation injury [73] and also suppresses doxorubicin-induced apoptosis of cardiomyocytes in vitro [74]. Moreover, the cardiac gene transfer of IGF-I resulted in reduced infarct size after ischemia-reperfusion injury in vivo [75]. Of note, IGF-I transgenic mice presented with preserved left ventricular contractility in aging animals, which was associated with the improved regenerative capacity of cardiac stem cells [76]. In patients with chronic left heart failure, a single intravenous infusion of IGF-I resulted in decreased afterload (i.e. decreased systemic vascular resistance), it induced positive inotropic effects and thereby improved cardiac index. However, it did not influence PAP and PVR [77].

In the animal model of monocrotaline-induced PAH and in patients with IPAH an increased level of IGF-I was measured in the hypertrophied RV and in the explanted lungs [78,79]. The pathophysiological significance of these findings is currently unclear. In young, but not in adult mice suffering from PH induced by hypoxia or pressure overload, the genetic inactivation or the pharmacological blockage of IGF-IR was associated with improved right heart function [79]. Nonetheless, an increase in IGF-I expression in right ventricular cardiomyocytes was associated with the significant improvement of cellular cross-sectional area [80]. Importantly, adaptive right ventricular hypertrophy (due to hypoxia or pressure overload) was associated with the increased expression of IGF-I, which was, however, missing in a rat model of right heart failure [37].

Platelet-derived growth factor (PDGF)

Four polypeptide chains with a common structure have been described in the PDGF family, namely PDGF-A, PDGF-B, PDGF-C and PDGF-D. They form dimers through disulfide bonds creating the isoforms of PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. The PDGF receptors PDGFR-α and PDGFR-β are transmembrane tyrosine kinases with different affinities to these ligands. PDGF-B, PDGF-C and PDGF-D can bind to both receptor subtypes, whereas PDGF-A is restricted to PDGFR-α. These receptors induce cellular growth during embryogenesis, carcinogenesis and also in vascular development, where they promote proliferation and survival of vascular mural cells [81].

The involvement of PDGF in vascular remodeling during the development of PAH has extensively been studied (for more details see [82]). The expression of PDGFR is upregulated and its phosphorylation is elevated in the remodeled pulmonary arterioles of patients with PAH. These changes lead to the abnormal proliferation and migration of murine vascular smooth muscle cells, which is dependent on PI3K and phospholipase C-γ signaling [83]. The same authors found in a murine model that blocked or impaired PDGF signaling was protective against the development of PH and right ventricular hypertrophy induced by chronic hypoxia. Others described the critical involvement of sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) in the PDGF-mediated proliferation of rat PASMC, and pre-silencing of SphK1 could reverse cell proliferation [84]. It has been demonstrated that imatinib, a multi-tyrosine kinase inhibitor including PDGFR could reverse PAH in animal models (monocrotaline-induced or hypoxic PH). Furthermore, in the monocrotaline rat model imatinib therapy reversed hemodynamic changes and vascular remodeling [19]. Therefore, blocking PDGF signaling seemed a potential drug target. Although imatinib as an add-on therapy for 24 weeks might convey some clinical benefit (an increase in six-minute walking distance) as shown by a clinical trial in patients with PAH [85], a 3-year open label trial demonstrated a high burden of complications with a number of unexpected cases of subdural hematoma discouraging the use of imatinib therapy in PAH [86].

There is also evidence that the PDGF pathway can also induce cardioprotective effects in heart conditions. In a murine model of cardiac ischemia the pharmacological blockage of both PDGFR-α and PDGFR-β led to defective angiogenesis and increased permeability of new vessels in the infarcted area [87]. Rat cardiomyocytes under hypoxia upregulate PDGF-BB, which promotes cell survival [88]. It was also shown in engineered heart tissue that PDGF-BB stimulation conveys an anti-apoptotic effect and promotes contractility through PI3K-Akt signaling [39]. Pre-treatment with PDGF-AB decreased infarct size after coronary occlusion in animal models, which was related to the production of VEGF by cardiac endothelial cells [89]. In a rat myocardial infarction model the sequential delivery of VEGF and PDGF resulted in improved cardiac function, ventricular wall thickness and angiogenesis, as well as better cardiac muscle survival in the infarcted zone [90]. The local administration of PDGF to the myocardium by means of nanofibers in rats led to PDGFR-β phosphorylation and sustained improvement in cardiac function after experimental myocardial infarction [91]. Interestingly, stem cells overexpressing VEGF and PDGF migrate to the site of myocardial infarct to decrease its size, improve angiogenesis, cardiac function and exercise capacity as shown in rats [92]. Data in PAH are very limited; however, a decrease in serum PDGF-AA and PDGF-BB concentrations were found in IPAH compared to control subjects [93]. Future studies should give more insight into the potential beneficial effect of PDGF on cardiac function in PAH.

Clinical outlook

As circulating biomarkers, GFs might be reflecting cellular changes both in the pulmonary vasculature and cardiomyocytes in the RV. Therefore, they can aid the diagnosis of PH in early stages of disease in populations at high risk such as family members of patients with hereditary PAH, subjects with scleroderma or HIV. As some GFs, particularly VEGF or FGF-2 have been positively associated with right ventricular function, they might be early signals of deterioration in right heart function before overt decline can be detected by cardiac imaging. Moreover, as biomarkers of cardiac function in a composite model they might complement patient stratification to monitor and predict disease progression, which is an important clinical goal during disease management. In this way clinicians can be guided to timely escalate treatment for the long-term benefit of patients.

In spite of the limited evidence, GFs may also be drug targets as they potentially attenuate pulmonary vascular remodeling and also have beneficial effects on cardiomyocyte function and the RV adaptation process. However, contradictory effects of GFs, such as of FGF-2 and PDGF on vascular remodeling and cardiac function have been described. Hence, further clarification on the involvement of GFs in the development and progression of PH is warranted with the possibility that these pathways might be specific for certain subtypes of PH.

Pulmonary vasodilators including endothelin receptor antagonists, phosphodiesterase-5-inhibitors and prostacyclins are available during the management of PAH. The interaction of these drugs with GFs can be hypothesized as they might modulate the same intracellular signaling pathways or interfere in other ways, like in the case of TGF-β, which is involved in the regulation of endothelin expression in the pulmonary vasculature [94]. Treprostinil, a prostacyclin analog was shown to interfere with PDGF signaling, as it improved PDGF-induced remodeling parameters in PASMCs isolated from patients with PAH. Treprostinil treatment reduced TGF-β and connective tissue GF secretion from these cells via the increased levels of cyclic adenosine monophosphate [95]. Currently available drugs do not directly target cardiomyocyte function; however, as GFs might exert such effects, a combination therapy may have a dual influence and provide better survival than pulmonary vasodilators alone.

Conclusions

The mechanisms behind the development and progression of PAH are incompletely understood, with even less knowledge on pathways regulating right ventricular dysfunction. Although the preservation of right heart function is associated with better clinical prognosis, currently no therapies specifically target and improve right ventricular function. Experimental and human studies equivocally described the involvement of GFs such as VEGF, TGF-β, FGF-2, IGF-I and PDGF in the development of PAH, but other studies (both in other cardiac disorders and in PAH) suggested that these mediators can exert beneficial effects on cardiac function. Among their multiple effects, these mediators support hypoxia-induced angiogenesis, restrict hypoxemia-related cardiac injury, promote adaptive hypertrophy and inhibit apoptosis of cardiomyocytes. These observations can pave the way to explore novel therapeutic targets to preserve or predict the progression of right heart function in patients with PAH.

Acknowledgments

This work was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences to Zsófia Lázár (under Grant No. BO/00559/16); and the Hungarian Respiratory Foundation to Györgyi Csósza (under Grant No. MPA/2019).

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  • 1.

    Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, . 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46: 90375.

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