Shao-Fei Liu1,2†
Netra Nambiar Veetil1,2,3†
Qiuhua Li1,2
Mariya M. Kucherenko1,2,3*
Christoph Knosalla2,3,4
Wolfgang M. Kuebler1,2,5,6,7- 1Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- 2German Centre for Cardiovascular Research (DZHK), Berlin, Germany
- 3Department of Cardiothoracic and Vascular Surgery, German Heart Center, Berlin, Germany
- 4Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- 5German Center for Lung Research (DZL), Gießen, Germany
- 6The Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada
- 7Department of Surgery and Physiology, University of Toronto, Toronto, ON, Canada
Pulmonary hypertension (PH) is a progressive disease that arises from multiple etiologies and ultimately leads to right heart failure as the predominant cause of morbidity and mortality. In patients, distinct inflammatory responses are a prominent feature in different types of PH, and various immunomodulatory interventions have been shown to modulate disease development and progression in animal models. Specifically, PH-associated inflammation comprises infiltration of both innate and adaptive immune cells into the vascular wall of the pulmonary vasculature—specifically in pulmonary vascular lesions—as well as increased levels of cytokines and chemokines in circulating blood and in the perivascular tissue of pulmonary arteries (PAs). Previous studies suggest that altered hemodynamic forces cause lung endothelial dysfunction and, in turn, adherence of immune cells and release of inflammatory mediators, while the resulting perivascular inflammation, in turn, promotes vascular remodeling and the progression of PH. As such, a vicious cycle of endothelial activation, inflammation, and vascular remodeling may develop and drive the disease process. PA stiffening constitutes an emerging research area in PH, with relevance in PH diagnostics, prognostics, and as a therapeutic target. With respect to its prognostic value, PA stiffness rivals the well-established measurement of pulmonary vascular resistance as a predictor of disease outcome. Vascular remodeling of the arterial extracellular matrix (ECM) as well as vascular calcification, smooth muscle cell stiffening, vascular wall thickening, and tissue fibrosis contribute to PA stiffening. While associations between inflammation and vascular stiffening are well-established in systemic vascular diseases such as atherosclerosis or the vascular manifestations of systemic sclerosis, a similar connection between inflammatory processes and PA stiffening has so far not been addressed in the context of PH. In this review, we discuss potential links between inflammation and PA stiffening with a specific focus on vascular calcification and ECM remodeling in PH.
Introduction
Pulmonary hypertension (PH) comprises a group of diseases in which the mean pulmonary artery pressure (mPAP) exceeds 25 mmHg at rest according to current guidelines (1). Recently, the 6th World Symposium on PH has recommended to lower this cutoff further to 20 mmHg (2). The World Health Organization (WHO) classifies PH into five groups based on identifiable cause and risk factors (3). Although the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) has entered the stage of targeted therapy, the 5-year survival rate of patients with PAH is still only approximately 50% (4), presumably due to the multifactorial pathophysiological mechanisms of PAH, which evade targeting by a single pharmacological drug, in particular at the advanced disease stage (5). Therefore, identification and therapeutic targeting of common upstream mechanisms that trigger multiple downstream cellular and molecular processes governing pulmonary vascular remodeling in different PH groups remains the ultimate goal for an improved care of PH patients.
Lately, pulmonary perivascular inflammation has gradually gained increased attention as an early common hallmark across different PH groups. In the early stage of the disease, PAH patients and corresponding animal models not only display an accumulation of immune cells such as macrophages (6, 7) and mast cells (8) in their lungs (9), but also have elevated levels of inflammatory mediators in their pulmonary circulation (10, 11) (Figure 1). In most forms of PH, this inflammatory response is predominantly localized to the pulmonary adventitia (7). In fact, changes in the adventitia, which consists of a complex mix of heterogeneous cells, tend to precede those in other vascular compartments and are required for vascular remodeling (12). In PAH, this spatial predilection has been linked to the fact that fibroblasts in the pulmonary adventitia exhibit a pro-inflammatory phenotype with an increased expression of inflammatory mediators that drive the recruitment of innate immune cells (7, 13, 14). The resulting perivascular inflammation is now considered to constitute a critical pathomechanism orchestrating remodeling from the outside-in not only in PH associated with disorders of the immune system, such as connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) (15), but also in other forms of PAH (11, 16) as well as in PH due to left heart disease (PH-LHD) (17). In parallel, the adventitia releases a myriad of factors that regulate differentiation, proliferation, apoptosis, migration, and collagen synthesis by other cells in the vessel wall, while adventitial fibroblasts can transform to myofibroblasts and migrate into the intima through the medial layer (12). As such, it has been proposed that inflammatory processes alter vascular and immune cell metabolism, ultimately enhancing pulmonary artery (PA) remodeling and aggravating PH (Figure 1).
Figure 1 Proposed role of inflammation in PA stiffening; The development of PH is associated with an inflammatory response in the pulmonary vasculature, characterized by immune cell infiltration and the secretion of immune factors. ECM stiffening, especially proximal large pulmonary vascular sclerosis, occurs in the early stages of PH and has a prognostic value for patient outcome and later calcification, and is driven by inflammation. Prolonged angiosclerosis, in turn, further promotes an inflammatory response that exacerbates pulmonary vascular calcification and thickening. PH, pulmonary hypertension; ECM, extracellular matrix; PA, pulmonary artery.
Concomitantly over the past decade, PA stiffening has emerged as an early hallmark, pathomechanism, and predictor of morbidity and mortality in PH (18–20). Vascular stiffening, defined as increased resistance of the arterial wall to deformation during blood influx, is a consequence of pathological vascular remodeling that can occur in both large proximal arteries and small distal arteries and arterioles. The mechanical consequences of these structural changes are decreased compliance in proximal PAs, and increased resistance to blood flow (pulmonary vascular resistance, PVR) in distal PAs (21). PA compliance (PAC) is essential to transform the pulsatile blood flow that enters the large conduit arteries via the Windkessel effect into the nearly laminar flow at the level of the distal pulmonary vascular tree. As such, PAC reduces right ventricular (RV) afterload and maintains near-constant lung perfusion over the cardiac cycle. In line with the impact of PAC for RV function, invasive or non-invasive assessment of PAC (or capacitance) has revealed PA stiffening in PAH patients as a sensitive predictor of pathological RV remodeling and mortality (21–24). It has further been proposed that stiffening of proximal PAs, through elevation of pulse-wave velocity and the shear stress exerted by the blood, promotes injury and remodeling in distal vessels, thus driving the pathology of PH in a positive feed-forward loop (25). Such interdependency between proximal and distal PA regions would predict that pathological remodeling should occur in parallel in large and small vessels. Indeed, work by Stuart R. Reuben first identified a hyperbolic relationship between PAC and PVR (26). The product of PAC × PVR yields the resistance–compliance (RC) time, which is considered to remain almost constant in PH patients of WHO class I (PAH), III (PH due to chronic lung disease), IV (chronic thrombo-embolic PH), or V (PH with unclear multifactorial mechanisms) and independent of medical therapy (27). Interestingly, however, for patients with WHO class II PH (PH due to left heart disease), RC time is reduced, i.e., for any given PVR, the corresponding PAC is lower as compared to PH patients from other causes. Notably, this reduction in RC time is also associated with an increase in RV afterload (27). This interesting finding may indicate distinct pathomechanisms and/or a higher degree of stiffening in proximal PAs in PH patients with underlying left heart disease as compared to other forms of PH; yet, this notion remains to be rigorously tested and mechanistically explored.
Conversely, mechanical communication between proximal PAs and the distal pulmonary vasculature may also promote restoration of pulmonary vascular homeostasis. Evidence of such a reverse remodeling process derives from a few clinical studies in patients with congenital heart disease and PH due to intracardiac left-to-right shunts causing lung overperfusion. In these patients, surgical banding of the PA—performed with the intent to protect the proximal PA from excessive pressure and flow—could successfully improve PH and, in some cases, reverse vascular remodeling in distal arteries (28, 29).
A growing number of studies reporting techniques to estimate stiffness of proximal PAs in vivo show promise for the use of PA stiffness estimates as a prognostic tool in PH. Most commonly, PA stiffness is estimated by calculation of pulmonary arterial capacitance as ratio of stroke volume over pulmonary pulse pressure, assessed by either cardiac catheterization or non-invasively by echocardiography (20, 30–37), or by calculation of a stiffness index as change in PA pressure (again assessed by right heart catheterization) divided by the corresponding change in PA diameter (determined by real-time imaging modalities, such as cardiac magnetic resonance imaging) (18, 38).
Artery stiffening in cardiovascular disease is mainly attributed to remodeling of the extracellular matrix (ECM) and/or calcification within the arterial wall (39–42) (Figure 1). In particular, PAH is characterized by remodeling of the ECM and thickening of all three layers of the PA wall (43), which ultimately reduces arterial compliance. PAs of PAH patients exhibit an increased deposition of interstitial collagen, including collagen I, collagen XIV, and basement membrane-specific collagens, especially collagen IV (43–45). Additionally, increased expression of other ECM proteins such as elastin and fibronectin, or the matricellular ECM protein tenascin-C by dedifferentiated adventitial fibroblasts has been reported in PAH patients (46). Increased production and deposition of ECM constituents in PAs is considered to occur as an adaptive response to increased digestion of medial and basement membrane (BM) ECM by matrix metalloproteinases (MMPs), which have been found to be increased in PAH (47) and IPAH patients (45). The elevated expression of collagens by endothelial cells (ECs), smooth muscle cells (SMCs), and adventitial fibroblasts is associated with increased collagen-cross-linking by lysyl oxidases (LOXs) (48). In addition, proteolytic enzymes also induce degradation of elastic fibers, which are challenging to rebuild despite increased elastin gene expression due to the multicomponent complex 3D structure of these fibers (49–53). As such, PA stiffening emerges as a progressive imbalance of collagen over elastin fiber components in the PA wall.
Vascular stiffening has also been attributed to vascular calcification (40), a pathological deposition of solid minerals within the intima or media of arterial walls (54) (Figure 1). Importantly, pulmonary vascular calcification has been associated with transdifferentiation of SMCs into osteogenic-like lineages, driven by the activity of the pro-osteogenic transcription factor Runt-related transcription factor 2 (RUNX2) (55). As such, increased nuclear expression of RUNX2 in PA SMCs not only activates expression of calcification-related biomineralization genes (56), but also promotes cell proliferation and resistance to apoptosis by activating hypoxia-inducible factor-1α (HIF-1α) (55).
Stiffening of proximal PAs in PAH patients (18, 57) increases pulse pressure and shear stress in the pulmonary vasculature. Of relevance, these alterations in biomechanical forces acting upon the lung vascular wall can induce pro-inflammatory responses in ECs of distal PAs (58, 59) and promote the aggregation of immune cells (58). This includes inflammatory cell recruitment and release of immune-cell-derived cytokines, such as IL-6 (60, 61) and TNF (62) and bioactive enzymes, including MMPs (46), which may, in turn, promote vascular remodeling and stiffening processes, thus establishing a progressive vicious cycle. Such interplay between inflammation-triggered signaling events that, in turn, initiate wound healing processes and ECM remodeling, ultimately culminating in tissue fibrosis and scar formation, is well established in cardiac and systemic vascular diseases (63–65). In PH, however, the cause–effect relationship between inflammatory signaling and vascular stiffening has so far neither clinically nor experimentally been addressed. As such, the present review aims to link known inflammatory responses in PH to processes related to vascular stiffening, namely, ECM remodeling and vascular calcification, identified in either PH or other vascular diseases and vice versa. Proposed links and relevant literature are summarized in Table 1 and will be discussed in detail below. As such, we intend to highlight the potential relevance of a pathophysiological axis between inflammation and PA stiffening, and to incite mechanistic studies to address this conceptual gap in our present understanding of PH.
Table 1 Inflammatory mediators associated with vascular stiffening.
Inflammation-induced arterial wall thickening and ECM remodeling
PA stiffening and inflammatory responses are both paramount characteristics of PH. While inflammation is commonly associated with PH in both animal models and clinical scenarios, little is known about the role of inflammation in inducing vascular remodeling in PH. Only a limited number of studies have so far addressed the role of inflammation in promoting the production of ECM components (154), namely, collagens (155), fibronectin (156), and tenascin-C (156) in PH. Yet, in other cardiovascular diseases, the connection between inflammation and increased vascular stiffness has been better characterized: here, inflammatory processes have been shown to promote arterial stiffening through a variety of mechanisms, including the induction of endothelial dysfunction and BM stiffening, increased proliferation of SMCs (49)—resulting in arterial wall thickening and reduced compliance—and remodeling and stiffening of the ECM in different segments of the arterial wall.
In PH, elevated pressure and high pulsatile flow as a consequence of reduced vascular compliance can be sensed by ECs of the pulmonary vascular bed. Specifically in hypoxia-induced PH, ECs produce elevated levels of the inflammatory cytokines IL-1β (9) and IL-6 (9, 60), and express increased levels of immune cell adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and P-selectin (9). Concomitantly, other vascular resident cells, such as SMCs and fibroblasts, respond to biomechanical cues by altered secretion of immune factors including inflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1), stromal cell-derived factor 1, and CCR5 (71) (Table 1). These inflammatory mediators can, in turn, induce PA remodeling and stiffening (9, 71, 157). While the links between increased inflammation and PA remodeling are so far little understood in PH, we will delineate in the following existing connections between key inflammatory signals and vascular stiffening in systemic cardiovascular diseases, with the aim to translate this knowledge into an advanced understanding of the potential role of inflammation in PA stiffening in PH.
Several key inflammatory signals induce PA remodeling by dysregulating the behavior and function of both ECs and SMCs in PH, ultimately leading to arterial wall thickening and stiffening. Among these, IL-6 and TNF were found to be increased in plasma, lung, pulmonary arteries and veins, as well as in PA ECs in both patients and animal models of various PH groups (Table 1). In PAH patients (60) and in PH-LHD rat models (61, 81), IL-6 contributes to PA remodeling by inducing medial wall thickening via SMC proliferation and muscularization of the distal pulmonary arterial tree due to migration of SMCs into precapillary arterioles (60, 61, 81) (Table 2; Figure 2), potentially affecting arterial compliance by increased wall thickening. In the pulmonary adventitia, fibroblasts activate recruited macrophages through paracrine IL-6 signaling, initiating a pro-inflammatory and pro-fibrotic phenotype that is associated with an increased inflammatory response and vascular remodeling in PH (7). Notably, IL-6 is a sensitive marker for systemic inflammation in cardiovascular disease (60, 88). In rheumatoid arthritis (164) and acute ischemic stroke (165), elevated levels of IL-6 in patient serum were associated with aortic stiffening as estimated by pulse-wave velocity, which could be significantly reduced by therapeutic infusions of the anti-IL-6 receptor antibody tocilizumab (164).
Table 2 Potential links between factors associated with PA stiffening and immune responses in PH.
Figure 2 Potential links between inflammatory mediators and mechanisms of pulmonary arterial ECM remodeling and vascular calcification in PH. As described in detail in the manuscript text, perivascular accumulation of immune cells is a characteristic feature of PH. Inflammatory cells such as macrophages produce MMPs that promote ECM degradation and remodeling. Inflammatory cytokines such as IL-6 and TGF-β drive the proliferation of PA SMCs. Stimulation of fibroblasts by inflammatory mediators increases the expression of collagens, elastin, and fibronectin, further promoting PA stiffness. Activated immune cells and inflammatory mediators promote SMC transdifferentiation and enhance the expression of biomineralization genes, thus driving vascular calcification. BMPR2 downregulation, especially in response to the inflammatory factor TNF, promotes endothelial cell mesenchymalization and may as such contribute to the development of pulmonary vascular calcification. A detailed discussion of the proposed signaling pathways is provided in the manuscript text. ECM, extracellular matrix; MMPs, matrix metalloproteinases; SMC, smooth muscle cells; PH, pulmonary hypertension; PA, pulmonary artery; BM, basement membrane.
Similarly, elevated TNF in rodent models of PAH and PH-LHD has been shown to result in increased PA EC and SMC proliferation and medial wall thickening (61, 166), which have been attributed to suppressed BMPR-II signaling in PAH (166). Due to its effects on SMC hyperplasia, TNF may also promote PA stiffening in PH; however, direct correlations between TNF levels and PA stiffness in PH have yet to be established. In other cardiovascular and inflammatory diseases, e.g., arteriosclerosis, TNF is an established key mediator of vascular remodeling (61, 62). Patients with inflammatory artheropathies, namely, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, who received anti-TNF treatment with either adalimumab, etanercept, or infliximab, showed a reduction in aortic stiffness as assessed by pulse-wave velocity and augmentation index as compared to untreated controls (107, 167). Hence, pharmacological inhibition of inflammatory mediators such as IL-6 and TNF in PH could potentially reduce pulmonary vascular cell proliferation and PA thickening and may therefore present a targeted therapy for PA stiffening.
Furthermore, pro-inflammatory mediators can induce vascular stiffening in cardiovascular diseases by increased production of ECM components, namely, fibrillar and non-fibrillar collagens and fibronectin by resident vascular cells (168). After myocardial infarction as well as in ischemic and non-ischemic heart failure, pro-inflammatory mediators such as TGF-β (74, 169) and IL-1β (170) induce the conversion of fibroblasts into myofibroblasts, which can produce abundant ECM proteins (168) (Tables 1, 2; Figure 2). In PH, adventitial myofibroblasts contribute to PA remodeling and stiffening (46) via the production of structural ECM components such as collagens, elastin, fibronectin, and dynamic ECM constituents, including tenascin-C and osteopontin (43, 46, 74) (Table 2; Figure 2). Tenascin-C and osteopontin, in turn, increase fibroblast and SMC proliferation, contributing to myofibroblast conversion and medial thickening, and therefore vascular stiffening (43, 46, 171) (Figure 2). Activated macrophages recruited to the pulmonary adventitia may express ECM proteins such as collagen type I, thereby contributing to ECM stiffening in PH (172). In animal models of MCT-induced PH, NADPH oxidase 4 (Nox4) has also been found to be upregulated in the pulmonary adventitia, where it promotes TGF-β-mediated expression of matrix collagens by adventitial fibroblasts and, as such, ECM stiffening (172). Similarly, collagen deposition by resident fibroblasts into the adventitia was also found to be increased in an animal model of chronic hypoxic PH and resulted in a thicker and stiffer arterial wall (172–174). In order to form insoluble rigid fibers, excessive fibrillar collagens are then further cross-linked by cross-linking enzymes (43, 175). Specifically, elevated expression of LOX in SMCs and lysyl oxidase-like enzyme (LOXL) expression in adventitial fibroblasts leads to increased collagen cross-linking and PA stiffening in PAH (176). Moreover, adventitial fibroblasts per se exhibit a pro-inflammatory phenotype in PH, including the recruitment and activation of adventitial macrophages (7) and production of pro-inflammatory markers, such as the chemokines MCP-1, SDF-1, RANTES/CCR5, CCR7, CXCR4, and the co-stimulatory molecules CD40 and CD40L (7, 71). This secretory activity can, in turn, create another feedback loop that triggers further inflammation and, hence, ECM remodeling.
Apart from elevated levels of circulating inflammatory mediators, increased mPAP in PH also induces activation of the pro-inflammatory NF-κB signaling pathway in PA ECs and SMCs (58, 133, 157) (Figure 2). Based on studies in systemic cardiovascular diseases, such activation of NF-κB emerges as a potentially important step in PA stiffening. As such, nuclear NF-κB was shown to increase the expression of aortic collagen type I in a murine model of type 2 diabetes, resulting in aortic stiffening as measured ex vivo by pressure myography (177). Interestingly, these effects were mediated by an NF-κB-dependent overexpression of RUNX2, a key transcription factor relevant not only for ECM remodeling [through increased expression of ECM collagens by SMCs (177)], but also in the context of vascular calcification (55, 177) (as discussed below) (Figure 2). It may be speculated that activation of NF-κB could exhibit similar effects in PH, thus contributing to PA stiffening through ECM remodeling and vascular calcification.
Inflammation-induced overproduction of ECM components in cardiovascular diseases is rivaled by elevated proteolytic ECM degradation via a parallel increase in MMPs (46). In PH, activated macrophages and myofibroblasts in the adventitia secrete MMPs, specifically MMP-2 (154, 162), MMP-9 (6, 162), MMP-10 (47), and MMP-19 (6, 154), while tissue inhibitors of metalloproteinases (TIMPs) appear downregulated (46, 162) (Table 2; Figure 2). MMP-2 (50) and MMP-9 (49) degrade elastin, thereby decreasing vessel compliance, resulting in arterial stiffening (49–52). Furthermore, degradation of elastic fibers and other ECM components such as BM collagens, interstitial collagens, fibronectin, and several proteoglycans by MMPs, facilitates migration of adventitial fibroblasts and myofibroblasts into the media and intima, which, in turn, promotes PA stiffening and vascular stenosis (46, 154) (Table 2). Similarly, neointimal formation via increased proliferation and migration of SMC from the media into the intimal regions of the arterial wall is likewise facilitated by MMP-regulated ECM degradation (52, 178) and promotes vascular stenosis and stiffening (178). Products of ECM proteolysis—the matrikines [recently reviewed in detail by Mutgan et al. (179)]—can, in turn, serve as pro-inflammatory mediators, which accentuate inflammation and may, as such, create another positive feedback loop (43). Furthermore, ECM degradation allows for circulating serum factors to enter the media and stimulate serine elastase production by SMCs (178). These serine elastases aid elastin degradation and the release of activated growth factors, such as fibroblast growth factor (FGF) and TGF-β that, in turn, increase collagen, fibronectin, and tenascin-C production by SMCs and fibroblasts (43)—again furthering PA stiffening (Table 2). In other cardiovascular diseases such as ischemic heart failure, immune cells like macrophages, lymphocytes, and mast cells secrete MMPs that remodel the vascular and cardiac ECM in response to mechanical stress (168). In arteriosclerosis, elevated levels of both MMP-2 and MMP-9 were associated with increased arterial stiffness and cardiovascular disease risk, which has been attributed to their ability to degrade the elastic laminae in arteries (180, 181). Accordingly, MMP-2 knockdown reduces arterial stiffening of carotid arteries in mice by decreasing elastin degradation in the tissue (182).
As such, activation of immune cells and inflammatory pathways, and arterial wall thickening and ECM remodeling may reciprocally stimulate each other. Targeting inflammatory processes in cardiovascular diseases, for example, aortic aneurysms, has shown beneficial effects on key mechanisms of ECM remodeling such as elastin degradation, MMP expression, and macrophage infiltration (183). As such, a better understanding of the specific players and molecular pathways involved in this mutual interaction may reveal novel and potentially personalized targets for future PH therapy.
Pulmonary arterial calcification and inflammation
Biologically induced mineralization is an integral part of human physiology and tissue homeostasis that involves extracellular and intracellular mechanisms to direct the nucleation, growth, and location of the deposited minerals. In disease conditions, these processes may become dysbalanced due to changes in the local or global calcium milieu, DNA damage, endoplasmic reticulum stress, oxidative stress, or metabolic disorders—i.e., processes that are frequently associated with inflammatory responses—and ultimately result in pathological tissue or blood vessel calcification (184, 185). Mechanistically, these factors lead to (or are accompanied by) phenotypic conversion of various cell types into osteoprogenitor cells via de novo or increased expression, respectively, of the potent transcription activator RUNX2, which triggers the expression of downstream calcification-promoting proteins such as alkaline phosphatase (186–188). In comparison to systemic arteries, vascular calcification of the PA is scarcely addressed, yet it is actually a common feature in patients with severe prolonged PH (189), advanced PH, and PH with chronic renal failure (190) or end-stage renal disease (191). In fact, detection of peripheral PA calcification by computed tomography (CT) (192) predicts long-term outcome in PH (193) and in patients with atrial septal defect and Eisenmenger’s syndrome (194).
In the context of PAH, a critical role in the regulation of PA calcification has been attributed to a microRNA-204-dependent upregulation of RUNX2 that, in turn, activates HIF-1α, leading to PA SMC hyperproliferation, resistance to apoptosis, and subsequent transdifferentiation into osteoblast-like cells (55). A second study reported that hypoxia-induced circular RNA CDR1 promotes osteogenic transdifferentiation of human PA SMCs by sponging microRNA-7-5p, and consequently upregulating its downstream targets calcium/calmodulin-dependent kinase II-delta (CAMK2D) and calponin 3 (CNN3) (195). Third, PA calcification has been linked to hypoxia, in that hypoxia decreases the expression of serine protease granzyme B stored in the granules of T lymphocytes and natural killer cells, which inhibits store-operated calcium channels (SOCCs) as the main source of calcium mineral by attenuating non-canonical Wnt signals in SMCs, thus increasing calcification of the PA (141). Independent of the underlying pathway, calcification ultimately increases vascular stiffness and reduces the compliance of the pulmonary arterial wall, which is a manifestation of poor prognosis in PH (21).
In the systemic vasculature, inflammatory signals—as seen in PH—have been shown to regulate vascular calcification processes. Specifically, TNF promotes osteogenic differentiation and calcification of bovine aortic SMCs by inducing the expression of osteoblast markers, such as osteoblast-specific factor 2 (Osf2), activator protein 1 (AP1), and cAMP-responsive element-binding protein (CREB) via activation of cAMP signaling (104). Likewise, treatment of aortic SMCs with IL-1β or IL-6 caused a dose-dependent increase in alkaline phosphatase activity and increased cell mineralization in vitro (196). Interestingly, expression of the inflammatory cytokines IL-6, TNF, and MCP-1 is epigenetically regulated in various tissues by bromodomain protein 4 (BRD4) (86), which modulates the chromatin landscape and activates gene expression by scaffolding transcription factors at gene promoters and/or superenhancers. Notably, BRD4 is upregulated in PA SMCs of PAH patients and in lungs or distal PAs of rat PH models, and is posttranscriptionally regulated by microRNA-204 (87), which is concomitantly involved in PA calcification (55), providing for an additional epigenetic link between inflammation and vascular calcification. More importantly, the RUNX2 gene promoter has been shown to be under direct control of BRD4 during osteoblast differentiation (197) as well as in cancer (198), suggesting that BRD4 may serve as a “master-regulator” of both inflammation and vascular calcification in parallel. In line with this notion, BRD4 inhibition attenuated pulmonary and coronary artery remodeling in experimental PH, and this protective effect was associated with reduced levels of IL-6 and MCP-1 (199, 200).
Although studies linking calcification and inflammation in PH are scarce, cytokines have been implicated in the regulation of calcification in the extra-pulmonary vasculature. Importantly, vascular calcification also seems to be closely interconnected with ECM remodeling and stiffening (201), as SMC mineralization directly correlates with the production of collagen I and fibronectin and elastin degradation, while the latter forms scaffolds for calcium incorporation (201–203). These findings suggest that upstream inflammation may also promote vascular calcification through ECM remodeling.
Pulmonary arterial endothelial-to-mesenchymal transition and inflammation
While our interrogation of vascular calcification processes has at large focused on SMCs, it is important to keep in mind that ECs are also involved. In various cardiovascular diseases, ECs lose their characteristic morphology and undergo a shift toward a mesenchymal phenotype (204), a process that is termed endothelial-to-mesenchymal transition (EndoMT) and that is notably modulated by inflammation. Specifically, inflammatory cytokines such as IL-1β or TNF have been shown to induce EndoMT in PA ECs. In turn, these EndoMT cells start to secrete inflammatory cytokines including IL-4, IL-6, IL-8, IL-13, and TNF at much higher concentrations as compared to normal PA ECs (205), thus establishing a potentially vicious feed-forward loop. In line with the notion of inflammation-driven EndoMT in PH, activation of the pro-inflammatory NF-κB signaling pathway in a mouse model of monocrotaline (MCT)-induced PH was found to upregulate miR-130a, which induced loss of bone morphogenetic protein receptor type 2 (BMPR2), increased expression of High Mobility Group AT-hook 1 (HMGA1), and ultimately EndoMT in lung microvascular ECs (206). It is important to highlight that although EndoMT has been extensively documented in pulmonary and systemic ECs exposed to inflammatory mediators in vitro, the extent and relevance of EndoMT in vivo in recent studies using lineage tracing technologies remains controversial: By use of double transgenic mice stably expressing green fluorescent protein (GFP) in all ECs, Suzuki and colleagues detected GFP in 14.3 ± 1.8% of mesenchymal (CD144-CD45-CD326-) cells, indicating substantial EndoMT (207). Similarly, endothelial lineage tracing using transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice revealed abundant endothelial lineage-marked cells in the neointima where they expressed smooth muscle α-actin and smooth muscle myosin heavy chain following induction of PH by monocrotaline pyrrole (208). Yet, a recent lineage tracing study in chronic hypoxia and allergen-induced models of lung vascular remodeling showed retention of endothelial lineage-specific marker expression profiles without any indication of cell-type conversion (209). Notably, the recognition of limited or partial EndoMT does not necessarily conflict with its potential functional relevance in PA stiffening, but simply suggests that this relevance may potentially relate more to the release of proliferative, hypertrophic, and profibrotic signals—i.e., mediators of processes that will ultimately promote PA stiffness—by partial EndoMT cells rather than to the actual generation of significant mesenchymal cell mass via this mechanism. Indeed, a similar role is increasingly recognized for epithelial–mesenchymal transition in tissue fibrosis (210).
Over and above that, EndoMT may link inflammation to vascular calcification and, thus, PA stiffening in PH. Specifically, studies in aortic ECs show that inflammatory cytokines such as TNF and IL-1β modulate EndoMT and downregulate the expression of BMPR2 and JNK signaling, thereby sensitizing ECs for BMP9-induced osteogenic differentiation that culminates in mineralization (141). Similar regulatory mechanisms may drive PA EC calcification in different types of PH, and PAH patients with BMPR2 mutations or BMP signaling pathway impairments (104) would be expected to be specifically vulnerable in this scenario given the association of impaired BMPR2 signaling with EndoMT (211). Lineage tracing studies in the systemic circulation support a role for EndoMT in vascular calcification, showing, e.g., that a subset of endocardial cells can undergo endocardial-to-mesenchymal transition resulting in calcification of mouse and human cardiac valves (212) or that vascular ECs can transition into osteogenic cells (213), which can be prevented by inhibition of glycogen synthase kinase 3 (GSK3) (214). The role of EndoMT (or partial EndoMT) in vascular calcification in the pulmonary circulation and in the contact of PH has, however, so far not been addressed.
Potential clinical relevance
While current PH therapies (i.e., prostacyclins, phosphodiesterase inhibitors, calcium channel blockers, endothelin receptor antagonists, or soluble guanylate cyclase stimulators) focus primarily on alleviating vasoconstriction as a symptomatic approach (215), the long-term therapeutic goal is to shift towards targeting mechanisms of disease onset and progression, including vascular remodeling and inflammation (215). In this regard, targeting the immune–PA stiffening axis may present a particularly promising strategy in light of the predictive and pathomechanistic role of PA stiffening in PH, and the armamentarium of immunomodulatory therapies already in clinical use or in development. In the systemic circulation, anti-inflammatory therapies have shown promise to reduce arterial stiffening in inflammatory artheropathies such as rheumatoid or psoriatic arthritis (167). Specifically, TNF antagonists, such as adalimumab, etanercept, or infliximab, represent established anti-inflammatory therapies in (auto-)immune conditions (216) that have explicitly lowered aortic stiffness in patients with inflammatory artheropathies (107, 167).
As such, immunomodulatory treatments are increasingly considered as potential therapeutic strategies for the treatment of PH. Yet, despite promising findings in preclinical models (8, 146, 215, 217), results from clinical trials have so far shown only modest benefit (149, 218, 219), thus stressing the need for more personalized approaches. Given the discussed link between immune responses, ECM remodeling, and vascular calcification, PA stiffness may present a promising biomarker to identify and monitor patients who may profit from immunomodulatory therapies; yet, assessment of PA stiffness in clinical trials is presently rare. Preclinical models, however, highlight the potential promise of anti-inflammatory therapies to target PA stiffness: For example, inhibition of carbonic anhydrases by acetazolamide or ammonium chloride (NH4Cl) as a potential treatment for inflammation in PH was able to prevent SMC dedifferentiation and proliferation in a Sugen5416/hypoxia rat model (220). Other anti-inflammatory therapies, such as treatment with resveratrol, were similarly able to prevent PA remodeling and stiffening in chronic hypoxic rats (215), while inhibitors of the renin–angiotensin system such as captopril or losartan reduced the production of ECM components including interstitial collagen and the expression of MMP-2 and MMP-9 in PAH, thereby attenuating PA stiffening (215). Hence, targeting inflammation with a specific focus on PA stiffness may provide for a pathomechanism-based and individualized therapy to treat PH—a notion that should be considered and, ideally, may be tested in appropriate preclinical and clinical trials.
Author contributions
S-FL, NNV, and MK conceived and wrote the original draft manuscript. QL drew the figures. MK, CK, and WK conceived and revised the manuscript. All authors contributed to the article and approved the submitted version.
Funding
WK was supported by grants from the German Research Foundation (CRC 1470, A04; KU1218/12-1) and the German Center for Cardiovascular Research partner site Berlin, CK was supported by the German Centre for Cardiovascular Research partner site Berlin and by the German Ministry of Education and Research (BMBF), NNV was supported by the Doctoral Scholarship from the German Centre for Cardiovascular Research and the German Cardiology Association (DGK), MK was supported by the German Foundation for Heart Research (F23/20), and S-FL and QL were supported by the China Scholarship Council (No. 202008350142 and No.202108080221).
Acknowledgments
Parts of the figures were generated with the help of BioRender.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: pulmonary hypertension, inflammation, vascular stiffness, vascular calcification, ECM remodeling
Citation: Liu S-F, Nambiar Veetil N, Li Q, Kucherenko MM, Knosalla C and Kuebler WM (2022) Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening. Front. Immunol. 13:959209. doi: 10.3389/fimmu.2022.959209
Received: 01 June 2022; Accepted: 14 September 2022;
Published: 05 October 2022.
Edited by:
Rizgar A Mageed, Queen Mary University of London, United KingdomReviewed by:
Robert Naeije, Université libre de Bruxelles, BelgiumMorgan Salmon, Michigan Medicine, University of Michigan, United States
Copyright © 2022 Liu, Nambiar Veetil, Li, Kucherenko, Knosalla and Kuebler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mariya M. Kucherenko, mariya.kucherenko@charite.de
†These authors have contributed equally to this work