Fibroblast Growth Factor (FGF) has been hypothesized to play critical roles in vascular development and response to injury. Attempts to test these hypotheses in vivo have produced results which are incomplete or inconsistent. The applicants propose to test these hypotheses using a mouse chimera approach which allows them to quantitate the role of a gene in vivo by directly comparing the behavior of cells which can or cannot express FGF2 or FGFR1. Combined with a direct evaluation of the effect of FGF2 overexpression and of FGF2 inactivation, this chimera approach will allow the investigator to determine the roles of FGF2 and FGFR1 in blood vessel development and in vascular response to injury and the formation of new vessels in adults. Chimera analysis will also allow for testing the hypothesis that FGF2 acts directly within the cell that synthesizes it, via an """"""""intracrine"""""""" pathway, and that this pathway makes a significant contribution to the effects of FGF2 in vivo. By combining these results with an ongoing chimera analysis of the role of PDGF, the applicant will be able to build a consistent data set that will make it possible to clearly distinguish between the role that each gene plays.
In Specific Aim 1 the applicant plans to use transgenic mice which overexpress FGF2 to determine whether availability of FGF limits vascular responses to injury. These studies will test the hypothesis that the magnitude of response to vascular injury is limited, in part, by the amount of FGF available in the tissue.
In Specific Aim 2 the applicant will use FGF2 knockout mice to determine the role of FGF2 in neovascularization and vascular response to injury. The applicant will test the hypothesis that FGF2 plays a more significant role in adult pathologies which produce cell injury which releases intracellular FGF2.
In Specific Aim 3 the applicant will use chimera analysis of FGF2 knockout mice to determine whether FGF2 acts, in part as an autocrine/intracrine growth factor in vivo. This will be done by determining whether FGF2 inactivation has a cell autonomous phenotype in vivo.
Specific Aim 3 is designed to use chimera analysis of FGFR1 knockout mice to determine and quantitate the role of FGFR1 in vascular development. The applicant will focus on the development and maturation of the cardiovascular system.
Specific Aim 5 is designed to use chimera analysis of FGFR1 knockout mice to determine and quantitate the role of FGFR1 in neovascularization and vascular response to injury. The applicant will test the hypothesis that FGFR1 regulates two processes important for vascular pathologies: the initial mitogenic stimulation of cells and the movement of cells into the intima and/or sites of neovascularization.
