Adhesion Signaling in Vascular Growth and Development

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DESCRIPTION (provided by applicant): Proliferation and migration of smooth muscle cells (SMC) are critical processes during vasculogenesis and blood vessel maturation and are important in the pathophysiology of several prominent cardiovascular disease states such as atherosclerosis, restenosis following balloon angioplasty, and hypertension. Evidence suggests that the mitogenic responses of SMC during development and disease are modulated by extracellular matrix (ECM) proteins and signaling through the integrin-associated protein tyrosine kinase, focal adhesion kinase (FAK). Interestingly, we have shown that the expression of FRNK (FAK Related Non-Kinase), a dominant-inhibitory form of FAK is restricted to SMC with particularly high levels observed in large blood vessels. We hypothesize that in SMC, FRNK regulates growth and development by modifying adhesion-dependent growth factor signaling. As such, FRNK may prove an effective therapeutic target for disregulated SMC growth following endovascular manipulation. We propose to employ biochemical and genetic approaches to characterize the role of FRNK in vascular growth and development. The specific aims of this proposal are as follows: 1) Define the mechanism by which FRNK attenuates growth factor and adhesion-dependent cell proliferation and migration in vascular SMC. We will characterize which SMC mitogens are regulated by FAK/FRNK signaling using DNA synthesis and chemotaxis assays and define the signaling pathways altered by FRNK overexpression. Particular emphasis will be placed on defining the mechanism by which FRNK attenuates growth factor signaling in SMC. 2) Study the in vivo regulation of FRNK expression during development. We will employ tissue-specific in situ approaches to characterize FRNK expression patterns in the developing mouse. 3) Evaluate a functional role for FAK/FRNK signaling in vascular growth and development. We will employ a transgenic gene targeting approach to determine the effect of SM-specific overexpression of FRNK on vascular development.