Influence of Mechanical, Cellular, and Molecular Factors on Collateral Artery Growth (Arteriogenesis)

Abstract

Abstract-Growth of collateral blood vessels (arteriogenesis) is potentially able to preserve structure and function of limbs and organs after occlusion of a major artery. The success of the remodeling process depends on the following conditions:(1) existence of an arteriolar network that connects the preocclusive with the postocclusive microcirculation; (2) activation of the arteriolar endothelium by elevated fluid shear stress; (3) invasion (but not incorporation) of bone marrow-derived cells; and (4) proliferation of endothelial and smooth muscle cells. Most organs of most mammals including man can rely on the existence of interconnecting arterioles in most organs and tissues with heart being the exception in rodents and pigs. Arterial occlusion lowers the pressure in the distal vasculature thereby creating a pressure gradient favoring increased flow through preexisting collaterals. This increases fluid shear stress leading to endothelial activation with cellular edema, upregulation of adhesion molecules, mitogenic-, thrombogenic-, and fibrinolytic factors, leading to monocyte invasion with matrix digestion. Smooth muscle cells migrate and proliferate and the vessel enlarges under the influence of increasing circumferential wall stress. Growth factors involved belong to the FGF family and signaling proceeds via the Ras/Raf-and the Rho cascades. Increases in vascular radius and wall thickness restore fluid shear stress and circumferential wall stress to normal levels and growth stops. Although increases in collateral vessel size are very substantial their maximal conductance amounts to only 40% of normal. Key Words: arteriogenesis Ⅲ shear stress Ⅲ monocytes Ⅲ vascular remodeling Ⅲ leukocytes A fter birth, blood vessel growth proceeds mainly by two different processes. Angiogenesis describes the growth of new capillaries by sprouting or intussusception and will be reviewed elsewhere in this issue. The driving force for angiogenesis is ischemia. In contrast, arteriogenesis is based on growth and remodeling of preexisting collateral anastomoses. These arterioarteriolar connections belonging to the arcade-like microvascular blood flow distribution system are recruited to function as collateral vessels after the occlusion of a major artery. The initial triggers of arteriogenesis are physical forces like fluid shear stress. Collateral vessel growth includes attraction and invasion of circulating blood cells, proliferation of vascular wall cells, and remodeling processes with digestion and rearrangement of the extracellular matrix and elastic lamina. This review will focus on the mechanisms involved in arteriogenesis.It has become common knowledge for many years that blood vessels regress when not constantly perfused, that they Original

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

“…In addition, by using both RRBS and mRNA‐Seq, we discovered a set of mechanosensitive genes whose expression correlates to gene promoter DNA methylation status. Gene ontology analysis of these genes identified a number of pathways crucial for EC mechanotransduction and arteriogenesis, including several metabolism, transcription, MAPK signaling, and cell transport pathways 31, 66. Of note, SIRT4 was involved in a number of these significantly overrepresented pathways (Figure S5).…”

Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve

“…Ischemia-triggered arteriogenesis is believed to mediate a series of factors including monocyte͞macrophage derived cytokines, such as monocyte chemotactic peptide 1 or VEGF, followed by changes in shear stress in preexisting collaterals that would activate eNOS acutely and induce its gene expression after chronic changes in blood flow as seen during exercise training (1,25). eNOS-derived NO can serve in its well known capacity as a vasodilator to reduce vascular resistance, improve blood flow, and maintain proportional remodeling of blood vessels during changes in blood flow (26).…”

“…In the coronary circulation and peripheral vasculature, ischemia-initiated opening of preexistent collaterals and arterialization of these immature vascular channels preserves blood flow and contributes to the extent of ischemic reserve capacity in the heart and leg (1). Therefore, understanding the molecular mechanisms of ischemia-initiated vascular remodeling and angiogenesis is important.…”

Multipotent adult progenitor cells sustain function of ischemic limbs in mice

“…We hypothesized that the improvement in muscle perfusion, function, and regeneration in mMAPC-U-grafted animals was in part the result of trophic factor production (8). Indeed, we found that, in vitro, mMAPC-U secreted substantial amounts of VEGF-A, PDGF-BB, IGF-1 (417 ± 8, 33 ± 3, and 198 ± 20 pg/10 5 cells/60 h, respectively), factors important for EC, SMC, and/or SkMB proliferation, and monocyte chemoattractant protein-1 (MCP-1) (25 ± 3 pg/10 5 cells/60 h), important for initiating collateral expansion (29). VEGF-A and IGF-1 protein could be detected in areas surrounding grafted cells in vivo (41% ± 2% of the mMAPC-U stained positive for VEGF; IGF-1 could be detected mainly in the vicinity of engrafted cells; Supplemental Figure 6).…”