Endothelium reduces DNA synthesis in isolated arteries

Abstract

We evaluated effects of endothelium removal and of endothelium-derived vasoactive agents on DNA synthesis and contractility in the isolated arterial wall. The experiments were performed on renal artery segments that had been 1) isolated from adult rats, 2) suspended in tissue culture for 3 days in the continuous presence of fetal calf serum, and 3) exposed for the last 24 h to 5-bromo-2'-deoxyuridine. Nuclear incorporation of this thymidine analogue was visualized by immunohistochemistry and used as an index of DNA synthesis. Tissue culture did not alter relaxing responses to guanosine 3',5'-cyclic monophosphate (cGMP)-generating agents but promoted relaxing responses to adenosine 3',5'-cyclic monophosphate (cAMP)-generating agents. It stimulated DNA synthesis in the endothelium, media, and adventitia. Mechanical removal of endothelium increased intra-arterial DNA synthesis. This was most prominent in the media. In preparations with endothelium, indomethacin and methylene blue did not enhance DNA synthesis. In segments that had been denuded of endothelium, atrial natriuretic factor, forskolin, iloprost, and prostaglandin E2, but not isobutylmethylxanthine or sodium nitroprusside, significantly reduced intra-arterial DNA synthesis. These data indicate that endothelium removal promotes the mitogenic response of the arterial wall to exogenous growth factors. This cannot be attributed to inhibitory influences of endothelium-derived relaxing factor or prostaglandins released by the endothelium under basal conditions.

Platelet-derived growth factor receptors on macrovascular endothelial cells mediate relaxation via nitric oxide in rat aorta.

“…Further (32), possibly by releasing nitric oxide (33) that may serve to counteract the direct proliferative effect that PDGF has on the smooth muscle. The loss of this internal control early in vascular diseases featuring abnormal endothelium-dependent responses may help explain the subsequent proliferation of smooth mus-cle cells that often occurs as a part ofthe vascular response and which characterizes the pathogenesis of these diseases.…”

Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell. Role of cyclic-nucleotides and angiotensin1 receptors.

“…In line with this interpretation, All-induced migration was not inhibited by interleukin-l1, in the presence of D-arginine. As indomethacin was present in all experiments, a contribution of prostaglandins can also be excluded (6,10,39).…”

“…In normal arteries, the endothelium maintains SMC quiescence by synthesizing growth inhibitors like NO and growth promoters like AII (1, 2, 9, 10, 51) in a balanced fashion. Removal or damage of the endothelium, on the other hand, results in migration and proliferation of SMC (9,10,51) suggesting that an intact monolayer of confluent endothelium normally has a net inhibitory influence on the underlying SMCs (9,10,51 ). NO together with other substances synthesized by endothelial cells most likely contributes to these effects.…”

“…Inasmuch as removal and/or dysfunction of endothelial cells results in migration, as well as proliferation of SMCs (9,10), endogenous NO probably exerts a net inhibitory influence on migratory, as well as proliferative behavior of SMCs (9,10). However, although the effects of NO on SMC proliferation have been studied previously (7,8,11), the effects of NO on SMC migration have not been evaluated.…”

Modulation of blood flow and tissue perfusion by endothelium‐derived relaxing factor

“…In other models, however, endothelial denudation promotes a mitogenic response to exogeneous growth factors that is not attributable to loss of EDRF or prostaglandin synthesis (De Mey, Dijkstra & Vrijdag, 1991). Shear stress may also modulate expression of platelet-derived growth factor mRNA and transforming growth factor-,/I mRNA by the endothelium, and thus both vascular cell and extracellular matrix production through an EDRF-independent mechanism (Hsieh, Li & Frangos, 1991;Ohno, Gibbons, Lopez, Dzau & Cooke, 1992).…”