Inhibiting development of microvessels withins coronary or peripheral vessel walls for restenosis/atherosclerosis prevention or therapy

#The present invention relates to compositions and methods for the preventing and/or treatment of restenosis and/or atherosclerosis.

#The present invention further relates to compositions and methods for inhibiting the development of microvessels within the wall of coronary and/or peripheral vessels.

#Microvessels can develop in response to angioplasty procedures and/or stent implantation, and develop during the development of atherosclerosis; and thus, the present invention relates to compositions and methods for inhibiting the development of microvessels within the wall of coronary and/or peripheral vessels in response to angioplasty procedures and/or stent implantation, and during the development of atherosclerosis

#The following Detailed Description, given by way of example, but not intended to limit the invention to specific embodiments described, may be understood in conjunction with the accompanying Figures, incorporated herein by reference, in which:

#FIG. 1 shows the microvascular angiogenic processes that occur during restenosis and atherosclerosis; and

#FIG. 2 shows the reduction of microangiogenesis by the compositions and methods of the invention.

#This invention is designed to employ gene therapy or protein delivery to prevent or treat restenosis, by inhibiting the development of microvessels (vasovasorum) in the injured vessel, insofar as angiogenesis occurring within the vessel wall is an important permissive determinant of neointimal development, and or vessel remodeling. The invention uses various anti-angiogenesis strategies to suppress angiogenesis, and thereby inhibit the development of restenosis and/or atherosclerosis.

#Angiogenesis involves the sprouting of capillaries from preexisting blood vessels and/or the development of new vessels. This process is controlled by the action of several angiogenic growth factors and their tyrosine kinase receptors. Two systems involving vascular endothelial growth factor (VEGF) and the angiopoietin-1 ligands, along with their specific receptors (VEGF-R1, VEGF-R2 and Tie-2 respectively), seem to have a unique and specific roll in the induction and maintenance of new blood vessel formation. The angiopoietin-2 ligand also appears to play an important role in the cascade of events leading to angiogenesis. Studies in mice carrying homozygous disruption in these receptors have demonstrated VEGF and angiopoietin-1 act in sequence: 1) VEGF, through VEGF-R1, induces endothelial cell-cell interaction, proliferation, and tube formation; 2) angiopoietin-1, through binding to its receptor Tie-2, elicits recruitment and interaction with peri-endothelial support cells, thus maintaining vessel integrity and stabilizing newly formed blood vessels. Angiopoietin-2 appears to be a functional antagonist of antiopoietin-1; ang-2 expression may be a necessary step in destabilizing an existing vessel, thereby allowing it to initiate new vascular buds and branches. Multiple studies have also demonstrated that members of the family of FGFs and their signaling cascades stimulate angiogenesis (see, e.g., Flugelman et al., Circulation 88(6):2493-500 (December 1993)). bFGF and aFGF are in lesions, suggesting that they may play a role in expansion of vasovasorum. It therefore appears that each of these ligands, through their specific receptors, control a specific, complementary function relating to endothelial cells that collectively accounts for a significant part of endothelial cell morphogenesis into mature, functional blood vessels.

#An analysis of the many cellular and molecular mechanisms involved in atherogenesis reveals a remarkable parallelism to the cellular and molecular mechanisms involved in restenosis. On these bases, it would appear that strategies designed to inhibit angiogenesis involving the vasovasorum in the patient undergoing angioplasty would, just as in atherosclerosis, also inhibit processes leading to restenosis. The end result would therefore be to inhibit restenosis.