Regulation of Integrins in Neovasculature Development

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DESCRIPTION (provided by applicant): The process of angiogenesis plays a crucial role in the pathogenesis of numerous diseases, including but not limited to tumor growth/metastasis, diabetic retinopathy, and in tissue remodeling upon injury. Angiogenesis is driven by Vascular Endothelial Growth Factor (VEGF) and cell adhesion receptors, integrins on endothelial and blood cells. We have shown that one of the crucial regulatory events in angiogenesis is the cross-talk between VEGF receptor 2 and aV¿3 integrin. However, the pathological consequences and structural requirements for this crosstalk have yet to be determined. We have shown that a number of integrin-dependent functions are controlled by Akt pathway. However, due to the complexity of downstream targets, the exact role of Akt isoforms in the regulation of distinct cellular events of angiogenesis remains poorly understood. As our specific hypotheses, we propose that VEGFR2/ aV¿3 complex is crucial for the regulation of integrin-dependent functions and for the overall angiogenic response; and that Akt kinase pathway plays a central role in regulation of integrin activity and extracellular matrix composition during pathological angiogenesis. The following Specific Aims are proposed to test these hypotheses. Aim 1: To determine the structural requirements and the biological role of the complex between ¿3 integrin and VEGFR2 in vitro and in vivo. In order to demonstrate the key regulatory role of the complex, we will disrupt it using recently generated and characterized compounds. The role of the ¿3/VEGFR2 complex will be assessed in angiogenesis-related assays in vitro. The role of the complex will be elucidated in vivo in implanted tumors, wounds and ischemic tissues. Special consideration will be given to the role of ¿3 integrin and ¿3/VEGFR2 complex in the regulation of bone marrow-derived cell recruitment to neovasculature. These studies will not only determine the basic mechanisms of angiogenesis, they will lead to the generation of a new anti-angiogenic strategy. Aim 2: To further elucidate the mechanisms of integrin and extracellular matrix regulation by Akt pathway. A) Using Akt-1 and Akt-2 null mice recently characterized by our lab, we will further elucidate the role of Akt signaling in the regulation of integrin activity. The role of Akt1/2 signaling in the regulation of integrin-dependent extracellular matrix expression and assembly will be determined. Since Akt1 influenced functions of numerous cell types involved in angiogenesis, we will define the role of endothelial Akt1 in angiogenesis. A detailed understanding of how successful collaboration occurs between an initiator of angiogenesis, VEGF, an effector system, the integrins, will create the basis for the development of novel therapeutic strategies in cardiology, vascular medicine and cancer treatment. PUBLIC HEALTH RELEVANCE: The major mechanism to adapt to regional ischemia resulting from myocardial infraction or peripheral vascular diseases is the development of new blood vessels, a process known as "angiogenesis". In cancer, inhibition of angiogenesis suppresses tumor growth. Angiogenesis is triggered by Vascular Endothelial Growth Factor and dependent on the functions of integrins receptors. In order to be able to "build" functional blood vessels or inhibit their formation, a detailed knowledge of the mechanisms of angiogenesis is required. The goal of this proposal is to assess the molecular and cellular mechanisms of angiogenesis with an emphasis on pathophysiologically relevant models.