Structure and Function of New Blood Vessels

Project: Research project

Project Details

Description

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.
StatusNot started