Dual Role of VEGF in Pretreated Experimental ePTFE Arterial Grafts B. Randone, M.D., Ph.D.,* G. Cavallaro, M.D.,* ,1 A. Polistena, M.D.,* A. Cucina, Ph.D.,* P. Coluccia,* P. Graziano, M.D.,† and A. Cavallaro, M.D., F.A.C.S.* *Department of Surgery “P. Valdoni,” University “La Sapienza,” Rome, Italy; and †National Cancer Institute “Regina Elena,” Rome, Italy Submitted for publication April 26, 2004 Background. Lack of endothelialization and abnor- mal smooth muscle cell (SMC) growth adversely affect the outcome of vascular synthetic grafts. The aims of our study were to investigate how a coating of extra- cellular matrix (ECM) and vascular endothelial growth factor (VEGF) might affect the endothelializa- tion rate, smooth muscle cells (SMC) proliferation, and myointimal hyperplasia in experimental arterial ePTFE grafts. Methods. In each of 30 male Lewis rats, a 1-cm-long ePTFE graft was inserted at the level of the abdominal aorta. Animals were randomized in five groups (six animals each): groups A and A1 received ePTFE grafts coated with a synthetic extracellular matrix (growth factor-reduced matrigel) containing VEGF; groups B and B1 received ePTFE grafts coated with synthetic ECM; and group C received ePTFE grafts alone. The grafts were explanted at 30 days from surgery for im- munohistochemical analysis. Results. Both endothelialization rate and myointi- mal hyperplasia were augmented in group A versus groups B and C, and these findings were statistically significant. SMC density resulted significantly higher in group A versus groups B and C, and this was associated with an altered expression of bFGF and TGF. Conclusions. Pretreating ePTFE grafts with syn- thetic ECM and VEGF results in better endothelializa- tion, but also in undesired higher SMC density and myointimal hyperplasia. © 2005 Elsevier Inc. All rights reserved. Key Words: vascular endothelial growth factor; ex- tracellular matrix; ePTFE grafts INTRODUCTION Neointimal hyperplasia is the major cause of late failure of small-caliber synthetic arterial grafts, while early failures are mainly due to thrombotic occlusion. Both phenomena are due to the lack of endothelial lining [1]. Also, long-term patent grafts exhibit only a partial endothelialization, usually confined to paraanasto- motic areas. From more than two decades, several studies have been processed to obtain fully endothelialized synthetic arterial grafts. After the pioneeristic attempts of endothelial seed- ing of the graft at implantation, in vitro endotheliali- zation appeared highly promising [2, 3]. The progress in cell culture technology allowed sat- isfactory results, in some way depending on the type of matrix used for precoating of the graft to facilitate adherence and growth of endothelial cells (EC): fi- bronectin and later on fibrin glue were preferred ma- trix substances [4]. Autologous in vitro endothelializa- tion of infrainguinal ePTFE grafts is a clinical reality allowing good long-term results [5]. However, availability of in vitro endothelialized grafts is confined to centers connected with laborato- ries where cell culture technology is routinely applied. The alternative research pathway followed in sev- eral centers is the engineering of synthetic grafts so that “spontaneous” endothelialization would occur, through the pretreatment of graft tissue with a matrix substance and also with molecules able to trigger and to maintain a controlled process of migration and pro- liferation of EC. Attempts to enhance the healing of arterial grafts have relied on native structures that are themselves a source of EC and on angiogenetic factors, like omentum or bone marrow [6, 7] or substances that would facili- 1 To whom correspondence and reprint requests should be ad- dressed at Department of Surgery “P. Valdoni,” University “La Sa- pienza,” Policlinico Umberto I, 00161 Rome, Italy. E-mail: antonino.cavallaro@uniroma1.it. Journal of Surgical Research 127, 70 –79 (2005) doi:10.1016/j.jss.2004.09.005 70 0022-4804/05 $30.00 © 2005 Elsevier Inc. All rights reserved.