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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003104-04
Application #
6043648
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F1))
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Tso, Colin; Martinic, Gary; Fan, Wen-Hua et al. (2006) High-density lipoproteins enhance progenitor-mediated endothelium repair in mice. Arterioscler Thromb Vasc Biol 26:1144-9
Welt, Frederick G P; Tso, Colin; Edelman, Elazer R et al. (2003) Leukocyte recruitment and expression of chemokines following different forms of vascular injury. Vasc Med 8:1-7
Horvath, Christopher; Welt, Frederick G P; Nedelman, Mark et al. (2002) Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ Res 90:488-94
Chen, Zhiping; Fukutomi, Tatsuya; Zago, Alexandre C et al. (2002) Simvastatin reduces neointimal thickening in low-density lipoprotein receptor-deficient mice after experimental angioplasty without changing plasma lipids. Circulation 106:20-3
Simon, D I; Liu, C B; Ganz, P et al. (2001) A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban. Catheter Cardiovasc Interv 52:425-32
Edelman, E R; Seifert, P; Groothuis, A et al. (2001) Gold-coated NIR stents in porcine coronary arteries. Circulation 103:429-34
Chen, Z; Woodburn, K W; Shi, C et al. (2001) Photodynamic therapy with motexafin lutetium induces redox-sensitive apoptosis of vascular cells. Arterioscler Thromb Vasc Biol 21:759-64
Resnic, F S; Blake, G J; Ohno-Machado, L et al. (2001) Vascular closure devices and the risk of vascular complications after percutaneous coronary intervention in patients receiving glycoprotein IIb-IIIa inhibitors. Am J Cardiol 88:493-6
Garasic, J M; Edelman, E R; Squire, J C et al. (2000) Stent and artery geometry determine intimal thickening independent of arterial injury. Circulation 101:812-8
Drachman, D E; Edelman, E R; Seifert, P et al. (2000) Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. J Am Coll Cardiol 36:2325-32

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