Structure and Function of New Blood Vessels

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Tumors must induce new blood vessels if they are to grow beyond minimal size. They do so by secreting angiogenic cytokines such as VEGF-A, FGF-2 and PlGF, and, paradoxically, angiogenesis inhibitors such as thrombospondins. However, the new vasculature that tumors induce is highly abnormal with respect to organization, structure and function. We hypothesize that these abnormalities result from imbalanced secretion of angiogenic cytokines or inhibitors. In fact, overexpression of VEGF-A triggers an angiogenic response that proceeds through a defined series of steps, each characterized by blood vessels with different structural and functional properties, many of which resemble tumor vessels. The experiments proposed here are designed to model tumor angiogenesis by expressing angiogenic cytokines and inhibitors, individually and in combination, to create a "virtual tumor," i.e., tumor-like vessels and stroma without tumor cells. Aim 1 will express VEGF-A, PlGF and FGF-2, alone, in combination and in combination with angiogenesis inhibitors (TSP-1, TSP-2) in newborn rat retina (a tissue undergoing normal developmental angiogenesis) and in normal adult tissue with a quiescent vasculature. These experiments will elucidate the mechanisms by which each cytokine induces angiogenesis and will compare the vessels so generated and their genesis with that of tumor vessels. Aim 2 will overexpress or block the expression of these same cytokines and inhibitors in tumors, a context that may yield significantly different blood vessels from those elicited by the same cytokine(s) in normal adult or developing tissues. Building on the results of Aims 1 and 2, Aim 3 will express VEGF-A and PlGF to induce blood vessels that so closely resemble tumor vessels that they can serve as tumor vessel surrogates. These will be used to identify genes that are differentially expressed in tumor versus normal blood vessels and that can serve as potential candidates for tumor imaging, anti-angiogenesis therapy and also elucidate angiogenesis signaling pathways in collaboration with Project 2.