Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis: History
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Contributor:
Jasni Viralippurath Ashraf
,
Ayman Al Haj Zen

Vascular smooth muscle cells in the adult vasculature are not terminally differentiated cells. They possess extensive plasticity such that it can be stimulated to undergo a structural and functional transition into proliferative/migratory/synthetic phenotype or undergo an extreme phenotypic change into osteochondrocyte-like cells, foam-like cells, and myofibroblastsas detected in atherosclerotic lesions. Nevertheless, SMC plasticity enables de-differentiated SMCs to re-differentiate back to a quiescent and contractile state according to their microenvironment. SMCs are the predominant cell type in collateral arteries that restores blood flow after significant arterial occlusion in peripheral arterial disease patients. They respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states.

  • vascular smooth muscle cell
  • phenotypic switch
  • arteriogenesis
  • collateral arteries
  • peripheral arterial disease

1. The Pathophysiology of Arteriogenesis after Ischemia

When a primary arterial trunk is occluded, it leads to a pressure drop downstream of the arterial network subsequently creating a pressure gradient across pre-existing collateral circulation and forcing the diversion of blood flow through the collaterals. The altered blood flow generates hemodynamic forces in collateral arterioles and arteries triggering two vascular responses: short-term vasodilation and long-term expansive vascular remodeling [1]. The short-term phase mediated by vasoactive molecules such as nitric oxide relax the smooth muscle cells leading to vasodilation [2]. The acute alteration of fluid shear stress induces the expression of chemokines and adhesion molecules by the endothelium [3]. Chemokines trigger the recruitment and attachment of circulating monocytes to activated endothelium that express adhesion molecules [4]. Monocytes transmigrate through the endothelium into the sub-intimal space where they transform into macrophages and produce inflammatory cytokines and growth factors such as transforming growth factor-β (TGFβ) [5], tumor necrosis factor-α (TNFα) [6], epidermal growth factor (EGF) [7], and fibroblast growth factor (FGF) [8]. The accumulation of macrophages has been reported in the perivascular area as well [9]. Eventually, these cytokines and growth factors diffuse into the medial layer of collaterals modulating the signaling pathways of SMC [10]. This results in SMC phenotypic switching that involves the SMC dedifferentiation from the quiescent contractile phenotype to a proliferative, migratory, and synthetic phenotype [11]. Growth factors and cytokines secreted from macrophages activate the proteolysis system for extracellular matrix (ECM) remodeling to further enhance SMC phenotypic switching [12].

Synthetic smooth muscle cells migrate from the media to the subendothelial space (intima) where they proliferate abundantly and produce ECM components including collagen, elastin, and proteoglycans to the subintimal space resulting in the formation of a new layer of SMC [11]. At this point, the collateral vessel has an approximately 25-fold larger diameter with a newly formed tunica intima, reconstituted tunica media, and thickened tunica adventitia that can restore blood flow up to 50% [13]. The increased vascular diameter is associated with the normalization of shear stress and mechanical strain on the vascular wall [14]. This reduced intravascular pressure in the collaterals impairs endothelial activation, attenuates inflammation, and causes synthetic SMCs to re-differentiate back into their contractile state, thus terminating the collateral growth process [15]. Concurrently, blood flow is reduced and gradually regresses in collaterals that fail to have mature arteriogenesis [16].

Upon successful arteriogenesis, the collaterals exhibit an extensive outward and hypertrophic remodeling, which is associated with the transformation of a small microvascular resistance vessel into a large conductance artery [17]. The smooth muscle cell is the primary cell type in this collateral remodeling [18].

2. Molecular Regulation of SMC Phenotype Switching

Vascular smooth muscle cells in the adult vasculature are not terminally differentiated cells. They possess extensive plasticity such that it can be stimulated to undergo a structural and functional transition into proliferative/migratory/synthetic phenotype or undergo an extreme phenotypic change into osteochondrocyte-like cells [19], foam-like cells [20], and myofibroblasts [21] as detected in atherosclerotic lesions. Nevertheless, SMC plasticity enables de-differentiated SMCs to re-differentiate back to a quiescent and contractile state according to their microenvironment [22]. Many environmental factors of SMC phenotype are identified such as growth factors, cytokines, hormones, blood flow shear stress, cell-to-cell interactions, and cell-to-matrix interactions. SMCs phenotypic switching is a critical event in the pathogenesis of arterial wall diseases such as atherosclerosis [23], aneurysm [24], hypertension [25], and post-angioplasty restenosis [26].

The molecular basis of sustaining the SMC contractile state has been explained by maintaining CArG–SRF– Myocardin complex [27]. Any headway to disrupt this complex leads to down-regulation of genes encoding for contractile proteins, thus inducing a phenotypic switch to a synthetic pathways [28]. Indeed, the expression of the contractile genes is controlled by multiple CArG elements located within their promoter-enhancer regions [29]. The transcription factor serum response factor (SRF) binds to a general sequence motif in the CArG element (CC(A/T-rich)6GG) to regulate the expression of marker genes [30]. Myocardin (MYOCD) is a potent coactivator of SRF and acts as a mediator of environmental cues on the expression of SMC contractile genes [31]. Myocardin-related transcription factors (MRTFs) [32] and ternary complex factors (TCF) [33] have also been identified to be cofactors of SRF. Prior work has shown that MYOCD and MRTFs respond to pro-differentiation stimuli through Rho GTPases-actin signaling [34][35], whereas TCFs respond to dedifferentiation stimuli through mitogen-activated protein kinase (MAPK) signaling [36].

Several pathways transduce signals from cell surface receptors or integrins in response to the surrounding environmental factors to maintain the contractile phenotype. The RhoA/ROCK signaling triggers actin polymerization increases post-translational modification of MRTFs and releases it to the nucleus to induce contractile gene expression [32]. TGFβ enhances nuclear translocation of SMAD proteins. Interaction with SMAD-binding elements (SBEs) in turn upregulates the expression of differentiation marker genes [37]. Insulin growth factor (IGF) acts through PI3 K/AKT signaling which relieves FOXO4-repressive effect on the CArG–SRF–myocardin complex leading to stable expression of contractile genes [38][39].

The loss of the contractile phenotype occurs via growth factors such as Platelet-derived growth factor-BB (PDGF-BB), FGF, and EGF that activate MAPK cascade via the Ras/Raf/MEK/ERK pathway. The MAPK activation can phosphorylate and activate TCF proteins such as Elk-1 to displace MYOCD or induce SRF-dependent transcription of early response growth, dedifferentiation genes, and repression of smooth muscle contractile genes [40]. ERK can phosphorylate MRTFs in the cytoplasm and prevent nuclear translocation [41]. PDGF-BB induces Kruppel Like Factor 4 (KLF-4) by binding to G/C repressor elements or by competing with SRF for CArG elements to disrupt CArG–SRF–myocardin [42][43]. Epigenetic regulation has been reported to control SMC phenotype switching [44]. For instance, the overexpression of histone acetyltransferase (HAT) enhances TGF β1-regulated SMC marker gene expression and its inhibitors such as Twist1 and E1A. Histone deacetylase (HDAC) expression converses this effect of TGF β1 in SMC [45]. Decreased DNA methyltransferase activity and DNA hypomethylation was observed in the proliferating intimal SMC present in the atherosclerotic lesions both in vivo and in vitro [46][47]. Although some recent advancement sheds light on to the influence of environmental cues in modifying epigenome, deeper research involving genome-wide profiling with epigenetic markers are warranted to completely understand its role in SMC phenotype switching in arteriogenesis.

3. The Effect of Hemodynamics on Smooth Muscle Cell Phenotype during Arteriogenesis

Upon arterial occlusion, the increase of blood flow and intravascular pressure in the bypass collaterals can generate two primary forces: fluid shear stress and circumferential wall tension [16]. The fluid shear stress force directly affects the endothelium [48]. Circumferential wall tension affects both endothelium and medial smooth muscle cells [49]. However, the fluid shear stress can indirectly affect the smooth muscle cells through diffusible vasoactive molecules secreted from activated endothelium, inflammation-induced shear stress factors, and shear stress generated by secondary interstitial flow [50]. Multiple in vitro studies have shown that both generated physical hemodynamic forces can influence the SMC phenotype [48]. Under physiological conditions, collaterals typically have little or no blood flow, and the fluid shear stress is minimal with little influence on the SMC phenotype [51]. Here, the phenotype of contractile SMCs in the collaterals is maintained mainly by the kinetic energy of flow, which is converted to potential energy that maintains the high circumferential wall stress of collaterals [52]. This also leads to an intense SMC investment of the collaterals unlike distal arterioles.

In contrast, after arterial occlusion, early vasodilation of collaterals leads to a rapid decrease in the intra-luminal pressure. Thus, according to Laplace’s formula, researchers expect that the circumferential wall stress would not change significantly in the early stage. In addition, the diminished blood pressure in downstream vessels is much lower than the proximal arterial pressure; thus, this pressure is unlikely to cause a significant stretch force on medial SMC at this phase. Indeed, the SMC in small arteries and arterioles generally react to the acute rise of intraluminal pressure by contraction (myogenic response) to regulate the tissue blood flow [53][54]. However, the collaterals are dilated after the arterial occlusion indicating that shear-mediated responses predominate the intravascular pressure-mediated responses or this could be partially explained by the fact that collaterals lack myogenic responsiveness and have less SMC tone at baseline than the arteries/ arterioles they interconnect [52]. Endothelial-smooth muscle cell co-culture studies have shown sustained exposure of endothelial cells to laminar shear stress inhibits SMC proliferation and induces a transition from a synthetic to a contractile phenotype [55]. These observations agree with in vivo animal studies showing an absence of SMC proliferation of the SMC phenotype switching at early stage (up to 48 hours after arterial occlusion) [56]. In summary, the increase in fluid shear stress is the dominant factor at the very beginnings where the SMCs are relaxed while maintaining their contractile phenotype.

Most collaterals tend to be tortuous small arteries [57]. The steady low shear stress is transformed rapidly to turbulent shear stress when blood flow increases after proximal arterial occlusion. The sudden changes in fluid shear stress naturally promote acute activation of endothelial cells and inflammatory pathways [58]. Endothelial cells sense the change of fluid shear stress via mechanosensors and covert this into paracrine chemical signals that influence the medial SMC [59]. The mechanosensation process involves multiple endothelial cell components. For instance, the activation of volume-regulated endothelial chloride channels is one of the earliest responses to endothelial cell swelling resulting from an acute increase in fluid shear stress [60]. Other early responses led to mechanically gated channels such as transient receptor potential cation channel V4 (TRPV4) and Piezo1. These are sensitive to changes in the endothelial cell membrane’s tension resulting from fluid shear stress [61].

In contrast, the alterations in the intraluminal pressure in the later stages of arteriogenesis can be extended to exert a mechanical force on the cellular components of VSMCs, which act as a mechanosensor to initiate subsequent signal transduction events [16]. Medial SMC can also be indirectly exposed to the fluid shear stress and blood flow pressure through the (transmural) interstitial flow. This flow shear stress is driven by the transmural pressure differential between the intra-arterial and tissue pressure [62] and can exhibit a direct shear stress force on SMCs that their mechanosensors can sense. Many mechanosensors were identified on VSMCs to sense the surrounding mechanical stimuli such as membrane-like receptors, ion channels and pumps, glycocalyx, primary cilium, and integrins [63][64]. These mechanosensors could transmit signals from the surroundings to affect the SMC phenotype as an adaptive response [65]. Hu et al. demonstrated that the adaptor molecules of membrane mechanosensors are inactive in the quiescent SMC. The altered mechanical stress initially induces a conformational change in the plasma membrane leading to autophosphorylation of PDGFα receptors and sequential activation of MAPK cascades [66].

4. Conclusions Remarks on Targeting SMC Phenotype Switching as Therapeutic Arteriogenesis

Arteriogenesis is a physiological remodeling response of the collateral arteries in the occlusive arterial diseases. Despite the dramatic outward remodeling of collaterals, blood flow is restored only up to 40–50% of the unblocked artery without intervention. One reason for the limited restoration of blood flow is the premature normalization of fluid shear stress (primary trigger of arteriogenesis). This natural compensatory capacity is diminished even further in subjects with co-morbid diseases such as diabetes [67]. Using an experimental shunting procedure, the induction of high continuous fluid shear stress in collateral circulation led to an increase in the maximal collateral conductance up to 80% of the maximal blood flow of the arterial tree before occlusion [68]. Indeed, this experiment is a clear proof-of-concept that a therapeutic intervention is feasible to enhance the natural arteriogenesis and overcome the anatomical and physiological limits of blood flow recovery after acute ischemia.

Vascular smooth muscle cells play a central role during arteriogenesis due to their plasticity. Phenotypic switching of the contractile VSMC to a synthetic state is a critical cellular event that sustains the growth and outward remodeling of collaterals. In contrast, VSMC re-differentiation back to their contractile state is important to regain vascular functions and prevent inappropriate hypertrophic remodeling of collaterals that could perturb the blood flow for distal ischemic tissues. The physiological normalization of fluid shear can lead to a premature switch of synthetic VSMC to a contractile quiescent phenotype; this switch eventually attenuates the collateral wall growth and remodeling. It has been shown that growth factor therapy can stimulate angiogenesis and also is able to stimulate arteriogenesis [69][70]. Many of the used growth factors such as FGF2 and PDGF are involved in the induction of SMC phenotype switching into synthetic phenotype. However, the single growth factor therapy was never able to completely restore the conductance capacity of a larger artery [71]. Thus, administration of vasodilators combined with agents inducing synthetic SMC as therapeutic strategy could increase the maximal collateral conductance in occlusive artery disease.

Targeting vascular smooth muscle cell phenotype switching has been suggested to be a therapeutic approach for tackling other vascular diseases such as atherosclerosis and hypertension. However, since the dynamics of VSMC phenotype switching are different in arteriogenesis, the timing of intervention would be challenging to achieve effective therapy. Another challenge of targeting VSMC in arteriogenesis is that several cellular events of atherosclerotic plaque development are also involved in arteriogenesis. For instance, extracellular matrix degradation, VSMC migration, and proliferation are activated in both arteriogenesis and atherogenesis. The stimulation of arteriogenesis through agents that promote VSMC proliferation or positive arterial remodeling could have side effects on the aggravation of atherosclerotic plaques in PAD patients who typically suffer from atherosclerosis. While many experimental studies have been conducted to investigate the molecular mechanisms of VSMC phenotype regulation in the context of atherosclerosis, the molecular mechanisms of VSMC phenotype switching that specifically control arteriogenesis in ischemic vascular disease remain largely unknown. Previous studies have been carried out to trace the VSMC phenotype dynamics in vascular repair and atherosclerosis models. Further studies are required for VSMC lineage tracing studies during arteriogenesis. These can help to identify novel specific molecular targets for therapeutic arteriogenesis of peripheral arterial disease patients.

This entry is adapted from the peer-reviewed paper 10.3390/ijms221910585

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