Accelerated arteriopathy following angioplasty or bypass surgery comprises primarily vascular smooth muscle cells, although other cells, particularly monocyte/macrophages, are active as well. Controversy exists, however, as to whether the main determinant of intimal thickening after these interventions is simply the initial lumen enlargement achieved, or whether mutable factors derived from vessel wall characteristics and from the form and extent of injury also participate. This grant proposes to use a model of endovascular stent-induced vascular injury characterized by intense monocyte recruitment to address this controversy. Stents offer a unique experimental tool as they hold lumen size constant, while causing predictable deep and superficial, acute and chronic injuries. Using a range of vascular biological techniques, 3 hypotheses will be tested: 1) Inflammatory cell recruitment and intimal thickening in vivo are determined by endothelial denudation and the depth/chronicity of injury, rather than by arterial enlargement alone. Using immunohistochemical techniques we will study determinants of monocyte recruitment and neointimal hyperplasia in arteries with injuries ranging from acute endothelial denudation to chronic deep injury. 2) Differences in monocyte recruitment to sites of different arterial injury are accompanied by alterations in of chemoattractant transcript and gene product expression. We will examine molecular mechanisms underlying the recruitment of monocytes to these injured arteries. 3) Modulators of vascular repair, such as heparin, inhibit monocyte adhesion in culture and in vivo, contributing to antiproliferative effects. A link exists between heparin's inhibitions of endothelium-independent monocyte adhesion and intimal growth. We will explore heparin's effects on monocyte adhesion to extracellular matrix proteins in vitro. My sponsor is Dr. Elazer Edelman, Associate Professor at Harvard Medical School and MIT, a leader in the study of vascular repair at the interface of materials, biology, and physiology. We have formulated a program with instruction in vascular biology to deepen my understanding of tissue biology and physiology while also broadening my training with the help of 2 Harvard collaborators: Dr. Mary Russell, a cardiologist-molecular biologist with long-standing interest in molecular immune mechanisms of vascular repair, will teach me molecular techniques adaptable to the proposed in vivo studies. Dr. Hal Chapman, a pioneer in monocyte- extracellular matrix interactions, will guide me in the adaptation of cell adhesion assays to study of monocyte biology pertinent to vascular injury. This intense study will enable progressively independent investigation of vascular biology with direct clinical applicability, providing added insight to the regulation of vascular repair.
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