E2F-mediated Control of Vascular Growth and Remodeling

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DESCRIPTION (provided by applicant): Vascular smooth muscle cell (VSMC) proliferation and migration following by-pass grafting and arterial angioplasty can lead to graft failure and restenosis. This pathological process is known as intimal hyperplasia. Limiting intimal hyperplasia in grafted vessels or a vessel following angioplasty is a critically important therapeutic target. A number of recent studies have attempted to limit VSMC proliferation and intimal hyperplasia by delivering inhibitors of cell cycle proteins to by-pass grafts or sites of angioplasty. One of the most promising approaches, developed by Dzau and colleagues, targets the E2F family of transcription factors for inhibition. A number of studies have shown that the growth suppression action of the retinoblastoma tumor suppressor protein (Rb) and other Rb family members is dependent on their ability to regulate the E2F family of transcription factors. It has also become increasingly clear that the E2F family of transcription factors can be divided into 2 subclasses based upon sequence homology and functional properties. The first subclass, containing E2F1, E2F2 and E2F3, are transcriptional activators that induce quiescent cells to proliferate. The second subclass, E2F4, E2F5 and E2F6 are important in the repression of E2F responsive genes and cell proliferation. Consistent with the repressor role of E2F4, we have recently determined that mice lacking E2F4 undergo accelerated intimal hyperplasia following arterial injury. Our Overall Hypothesis is that inhibition of individual (or subsets of the) E2Fs can reduce or enhance intimal hyperplasia following vessel damage or grafting and that a detailed understanding of how the various E2Fs control vascular smooth muscle cell proliferation during intimal hyperplasia will facilitate the development of more specific and potent inhibitors of this pathological process. Our Specific Aims are 1.) To determine the E2F family members that promote intimal hyperplasia and those that repress this pathological process using genetically modified mice, 2) To explore how perturbations in multiple E2F activities affect intimal hyperplasia and restenosis using genetically modified mice and 3) To develop aptamers that specifically target those E2F family that promote intimal hyperplasia and to evaluate the ability of these aptamers to limit intimal hyperplasia in animal models of vein graft failure and arterial restenosis Thus these experiments will delineate the E2F family member(s) that should be targeted for inhibition to reduce the occurrence of restenosis and vein-graft failure in humans and yield novel therapeutic compounds that may be useful in the treatment of individuals undergoing by-pass surgery or angioplasty.