Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery.

Abstract

This study investigated the vasodilator function of endothelium that regenerated after balloon angioplasty and the relation of this function to the extent of vascular injury and to subsequent intimal proliferation. Balloon angioplasty was performed in the left iliac artery of 47 New Zealand White rabbits. Vascular responses were examined in vitro 2 and 4 weeks after a "severe" injury (3.0-mm balloon) or a "moderate" injuiry (2.5-mm balloon). Both degrees of balloon injury caused complete endothelial denudation. Endothelial regrowth 2 weeks after either injury was confirmed histologically. Although the regenerated cells had irregular sizes and polygonal shapes and lacked the typical alignment in the direction of blood flow, immunocytochemical staining for factor VILI-related antigen identified these cells as endothelium. To study the vasodilator function of regenerated endothelium, rings of balloon-injured and control (contralateral) iliac arteries were suspended in organ chambers for recording of isometric force. Endothelium-dependent relaxation of balloon-injured vessels to acetylcholine and to the calcium ionophore A23187 were reduced at 2 and at 4 weeks after severe injury. After moderate injury, endothelium-dependent relaxations to these agents were reduced at 2 weeks but had normalized by 4 weeks. Endothelium-independent relaxation to sodium nitroprusside, however, was preserved in all study groups. Morphometric analysis revealed an inverse correlation between the degree of intimal thickening and maximal relaxation to acetylcholine (r=0.45,p<0.01). Thus, there is a persistent attenuation ofreceptor-and nonreceptor-mediated endothelium-dependent relaxations after arterial injury. The regenerated cells have an altered morphological appearance, but staining for factor VIII-related antigen confirms their endothelial origin. The degree and duration of endothelial dysfunction depends on the severity of the initial injury and is related to the extent of intimal thickness. (Circulation 1990;81:1667-1679 Normal endothelial function includes the formation of a semipermeable barrier that actively regulates coagulation, cell growth, and vasoreactivity.-4 Endothelium-derived relaxing

L-arginine improves endothelium-dependent vasorelaxation and reduces intimal hyperplasia after balloon angioplasty.

“…1 Electron micrographic studies demonstrate complete endothelium-denuding injury immediately after angioplasty, which corresponds to a complete loss of endothelium-dependent vasorelaxation and a tendency toward vasospasm and thrombosis. Endothelial regrowth generally occurs within 2 to 3 weeks; however, these regenerated endothelial cells display distinct morphological and functional alterations, with diminished production and release of NO and therefore, incomplete endothelium-dependent vasorelaxation.…”

“…Alterations in NO-mediated vasodilation persist in injured arterial segments even after regrowth of an endothelial cell monolayer. 1 Recent in vitro experiments have shown that NO inhibits platelet aggregation, leukocyte adhesion, and smooth muscle cell growth, all of which are key components in the development of intimal hyperplasia. 25 Furthermore, administration of L-arginine, the NO precursor, to hypercholesterolemic rabbits has been shown to reverse defects in NO activity and reduce the development of proliferative atherosclerotic lesions.…”

“…Previous studies have demonstrated that this technique results in complete removal of the endothelium from a segment approximately 2 to 3 cm long. 1 At the end of the procedure the angioplasty catheter was removed, the carotid artery ligated, and the wound closed.…”

Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction

“…In experimental models of vascular injury, there is attenuated endothelium-dependent vasodilation even after the intimal lining has been fully regenerated. 37 Recently, it has been shown that in regenerated endothelial cells, levels of ADMA (as well as another NO synthase inhibitor, L-monomethylarginine) are elevated 3-fold compared with normal cells. 38 The origin of ADMA in hypercholesterolemia is currently unclear.…”

Endogenous Nitric Oxide Synthase Inhibitor

“…20,34 Since L-arginine is abundant in endothelial cells, 52 depletion of this substrate is not likely to account for the endothelial dysfunction. 53 It is possible that endogenous NO synthase inhibitors may contribute to endothelial dysfunction; indeed, after balloon injury of the rabbit iliac artery, the regenerated endothelium manifests a vasodilator dysfunction, associated with markedly elevated levels of intracellular ADMA. 31 L-Arginine supplementation may overcome this competitive inhibition to restore endothelium-mediated vasodilation.…”