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Abstract
Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.
Highlights
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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) [32], tumor necrosis factor-α (TNFα) [33], epidermal growth factor (EGF) [34], and fibroblast growth factor (FGF) [35]
Ly6 Clow monocytes may differentiate into M2 macrophages, which secrete anti-inflammatory cytokines such as IL-10 and TGFβ1 and express growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, promoting collateral remodeling and expansion [143]
Summary
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. 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 [38] 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% [40]. The increased v cular diameter is associated with the normalization of shear stress and mechanical str on the vascular wall [41] This reduced intravascular pressure in the coll3aotfe1r7als imp endothelial activation, attenuates inflammation, and causes synthetic SMCs to re-dif esntrtaiainteobnatchke ivnatsocuthlaerirwcaolln[t4r1a]c.tiTlehisstareted,utcheudsintetrramvainscautlianrgptrheesscuorlelaintetrhael gcorlolawtetrhalpsrocess [ Cimonpcauirrsreenndtolyth, ebllioaloadctfilvoawtioins,raetdteuncueadteasnindflgarmamduatailolny, raengdrecsasuessesinsycnotlhlaettiecrSaMlsCthsatot fail to h mrea-dtuifrfeeraenrtteiartieogbeacnkesinisto[4th3]e.ir contractile state, terminating the collateral growth pfariolcteoUsshpa[o4v2ne].msCuaoctnuccreeusrsarfreutneltrliayo,rgbteelnoreoiosdigsfle[o4nw3e]s.isisr,edthuececdoallnadtegrraadlsuealxlyhirbegitreasnsees xintecnolsliavteeraolus tthwaat rd and pertrUoppohnicsureccmesosfduellairntegr,iowgheniceshisi,sthaescsoolclaitaetreadls wexihtihbitthaen etrxatennssfivoermouatwtioarndoafndahsympearl-l microv cturolaprhircerseimstoadnecleinvge, wssheilchinitsoasasolaciragteedcwonitdhuthcetatnracnesfaorrtmeraytio[n44o]f.aTshmeasllmmoicortohvamscuuslacrle cell is prreismistaarnycecveelslsteylpinetoina ltahrigsecconlldautecrtaanlcreeamrtoerdye[l4i4n]g.
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