Michael Simons, MD [ View bio ](Yale University, New Haven, Connecticut)
Arteriogenesis or the formation of arterial conduits is a promising therapeutic approach to the treatment of a number of ischemic vascular diseases. However, the molecular basis of this process remains poorly understood. Early attempts at therapeutic revascularization using various angiogenic growth factors and/or cell populations have fairly uniformly failed putting into question the overall feasibility of this approach. However, newer discoveries about the molecular nature of arteriogenesis provide firm foundation for clinical translation.
In adult tissues arteriogenesis can occur by the growth of collateral arteries from pre-existing arteriolar anastomoses or by de novo formation of new arteries through capillary arterialization. While it occurs at sites of arterial occlusion where ischemia is not prominent, VEGF receptor 2 (VEGFR2) activation has been shown to be pivotal to this process. Remarkably, the "arteriogenic" part of VEGFR2 signaling requires receptor internalization and trafficking. Any breakdown in any of the steps involved in these processes results in selective arteriogenic defects that include decreased arterial tree branching and reduced lumen size. At the same time, direct targeting of key VEGFR2 processing steps can activate arteriogenic signaling in a ligand-independent manner. This allows design of therapeutic strategies that can bypass endothelial unresponsiveness, the most common reason for pro-angiogenic therapies failure in advanced cardiovascular disease patient populations.
Another critical factor in effective arteriogenic response is regulation of the newly formed arterial tree size and branching. Recent studies have placed NFκB-regulated HIF2α signaling at the center of this process via control of Delta/Notch signaling cascade. Manipulation of this axis allows another means of therapeutic modulation of arteriogenesis.
In summary, recent advances in our understanding of the biology of arteriogenesis are finally paving the way for effective clinical translation and development of novel therapeutic approaches that will benefit patients with advanced coronary, cerebral and peripheral arterial vessel diseases.
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