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Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts

Richard D. Kenagy, Jens W. Fischer, Stephanie Lara, John D. Sandy, Alexander W. Clowes and Thomas N. Wight

Department of Vascular Surgery (RDK,AWC), and Department of Pathology (SL,AWC), University of Washington, Seattle, Washington; Molecular Pharmacology, Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany (JWF); Shriners Hospital and Department of Pharmacology, University of South Florida, Tampa, Florida (JDS); and The Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington (TNW)

Correspondence to: Richard Kenagy, PhD, Department of Surgery, University of Washington, 1959 N.E. Pacific St. Box 356410, Seattle, WA 98195-6410. E-mail: rkenagy{at}u.washington.edu

The composition of extracellular matrix during growth and regression of the neointima was analyzed during healing in a baboon aorto-iliac polytetrafluoroethylene graft. Graft neointimal thickening can be modulated by altering blood flow by construction of downstream arteriovenous fistulas. Normal flow with normal shear stress induces neointimal thickening, whereas high flow with high shear stress upstream of a fistula induces regression of established neointima. The neointima formed under normal shear stress is enriched in hyaluronan and proteoglycans, particularly versican. On the other hand, the neointima near the graft material is enriched in collagen and biglycan. Neointimal regression in response to high shear stress is associated with a loss of proteoglycans as detected by histochemical staining. Immunostaining with an antibody against an ADAMTS cleavage neoepitope of versican increases after switching to high flow, although immunostaining for versican core protein is not appreciably changed by high flow. The present data demonstrate that the graft neointima is enriched with proteoglycans, particularly versican and hyaluronan, as well as collagen, and there is a differential distribution of each. Neointimal atrophy occurs with an apparent loss of proteoglycans and evidence of versican degradation. (J Histochem Cytochem 53:131–140, 2005)

Key Words: neointima • proteoglycans • shear stress • smooth muscle cells • versican

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