Versican is differentially regulated in the adventitial and medial layers of human vein grafts.

Changes in extracellular matrix proteins may contribute significantly to the adaptation of vein grafts to the arterial circulation. We examined the production and distribution of versican and hyaluronan in intact human vein rings cultured ex vivo, veins perfused ex vivo, and cultured venous adventitial and smooth muscle cells. Immunohistochemistry revealed higher levels of versican in the intima/media compared to the adventitia, and no differences in hyaluronan. In the vasa vasorum, versican and hyaluronan associated with CD34+ progenitor cells. Culturing the vein rings for 14 days revealed increased versican immunostaining of 30-40% in all layers, with no changes in hyaluronan. Changes in versican accumulation appear to result from increased synthesis in the intima/media and decreased degradation in the adventitia as versican transcripts were increased in the intima/media, but unchanged in the adventitia, and versikine (the ADAMTS-mediated cleavage product of versican) was increased in the intima/media, but decreased in the adventitia. In perfused human veins, versican was specifically increased in the intima/media in the presence of venous pressure, but not with arterial pressure. Unexpectedly, cultured adventitial cells express and accumulate more versican and hyaluronan than smooth muscle cells. These data demonstrate a differential regulation of versican and hyaluronan in human venous adventitia vs. intima/media and suggest distinct functions for these extracellular matrix macromolecules in these venous wall compartments during the adaptive response of vein grafts to the arterial circulation

The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease

The extra cellular matrix (ECM) of the normal artery wall is a collection of fibrous proteins and associated glycoproteins embedded in a hydrated ground substance of glycosaminoglycans and proteoglycans. These distinct molecules are organized into a highly ordered network that are closely associated with the vascular cells that produce them. In addition to providing the architectural framework for the artery wall that imparts mechanical support and viscoelasticity, the ECM can regulate the behaviour of vascular cells, including their ability to migrate, proliferate and survive injury. The composition of the ECM is different within intimal lesions of atherosclerosis, which are composed of monocytes and lymphocytes from the circulation and smooth muscle cells (SMC) that migrate from the media to the intima (Ross 1993, 1999), and these differences may contribute to the altered phenotype of vascular cells within lesions. This review will briefly outline the ECM changes observed in atherosclerosis and restenosis and the potential relationship of these changes to altered vascular cell functions

The mechanisms of coronary restenosis: insights from experimental models

Since its introduction into clinical practice, more than 20 years ago, percutaneous transluminal coronary angioplasty (PTCA) has proven to be an effective, minimally invasive alternative to coronary artery bypass grafting (CABG). During this time there have been great improvements in the design of balloon catheters, operative procedures and adjuvant drug therapy, and this has resulted in low rates of primary failure and short-term complications. However, the potential benefits of angioplasty are diminished by the high rate of recurrent disease. Up to 40% of patients undergoing angioplasty develop clinically significant restenosis within a year of the procedure. Although the deployment of endovascular stents at the time of angioplasty improves the short-term outcome, ‘in-stent’ stenosis remains an enduring problem. In order to gain an insight into the mechanisms of restenosis, several experimental models of angioplasty have been developed. These have been used together with the tools provided by recent advances in molecular biology and catheter design to investigate restenosis in detail. It is now possible to deliver highly specific molecular antagonists, such as antisense gene sequences, to the site of injury. The knowledge provided by these studies may ultimately lead to novel forms of intervention. The present review is a synopsis of our current understanding of the pathological mechanisms of restenosis