Arteriogenesis describes the process of collateral vessel growth that is thought to be a critical biologic response to vascular occlusion. While clinical trials employing the """"""""therapeutic"""""""" administration of angiogenic growth factors have generally yielded disappointing results, it now appears that arteriogenesis may be more relevant than angiogenesis in creating a robust, large capacitance, stable neovasculature that can literally provide native """"""""bypasses"""""""" of vascular obstructions. In this regard, while ischemia/hypoxia are likely the primary physiologic triggers of angiogenesis, monocyte recruitment in response to vascular shear and other stresses has been implicated as a key early mediator of arteriogenesis. The molecular basis of this activation pathway is unclear, however, and while the arbitrary administration of growth factors may deleteriously bypass """"""""upstream"""""""" signaling pathways, an """"""""arteriogenic"""""""" transcription factor has yet to be identified. The EGR-1 transcription factor is responsive to changes in shear stress independent of the presence of hypoxia, and can activate a portfolio of potentially arteriogenic growth factors and molecules. In this context, we became intrigued by our demonstration of the rapid upregulation of EGR-1 expression following vascular occlusion, the near- absence of monocyte recruitment and reperfusion following vascular ligation in EGR-1 null mice, and the near-normalization of perfusion following EGR-1 administration to ligated wild type animals. We consequently speculated that EGR-1 is the """"""""missing"""""""" signal that transponds the physiologic sequelae of vascular occlusion into an (arteriogenic) neovascularization response. The current aims are therefore to test the hypotheses that EGR-1: 1) induces arteriogenesis as a critical response to vascular occlusion, by upregulation of key arteriogenic mediators, 2) induces monocyte recruitment as the catalyst for this response (and augment this process therapeutically), and 3) can """"""""therapeutically"""""""" induce stable revascularization greater than that induced by """"""""downstream"""""""" angiogenic mediators. To pursue these aims, we will use vascularization, perfusion and expression assays following vascular ligation in wild type vs. EGR-1 deficient (EGR-knockout or LacZ knock-in) mouse, rat and in a hypercholesterolemic swine myocardial ischemia models with or without VEGF, MCP-1 or EGR-1 administration, via acute or chronic (regulatable and tissue specific) gene transfer vectors. These studies should elucidate the microanatomic site and the locus in molecular signaling pathways of EGR-1 mediated regulation of revascularization, and provide pre-clinical data regarding the benefits of revascularization strategies via arteriogenic vs. angiogenic agents, and via a """"""""master switch"""""""" transcription factor vs. downstream mediators.

Public Health Relevance

Despite ongoing advances in the prevention and treatment of coronary and peripheral vascular disease, it is estimated that advanced disease limits the effectiveness or applicability of conventional therapies in approximately 50,000 - 80,000 individuals in the U.S. alone, who can be expected to die annually from coronary disease, and approximately 100,000 individuals will suffer limb loss from peripheral vascular disease. Interventions that can alter vascular biology and enhance the body's own ability to bypass itself by growing collateral vessels (arteriogenesis) therefore represent attractive alternatives to conventional therapies. Based upon a growing number of lines of evidence, we believe that a gene called Egr-1 may be a """"""""missing"""""""" signaling factor that can translate the physiologic (mechanical) stresses of vascular blockages into the growth of a stable and persistent new vasculature. This study seeks to elucidate the role of Egr-1 in native blood vessel growth and its potential use as a potent """"""""arteriogenic"""""""" revascularization agent.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Gao, Yunling
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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