Joint Program in Neonatology , Harvard Medical School , Boston , Massachusetts 02115 .
J Clin Invest 92 : 99-104 ( 1993)
Abstract
The mechanisms by which hypoxia causes vasoconstriction in vivo are not known .
Accumulating evidence implicates the endothelium as a key regulator of vascular tone .
Hypoxia induces the expression and secretion of endothelin-1 ( ET-1 ) , a potent vasoconstrictor in cultured human endothelial cells .
We report here that nitric oxide ( NO ) , an endothelial-derived relaxing factor , modifies this induction of ET-1 .
Whereas low oxygen tension ( PO2 = 20-30 Torr ) increases ET-1 expression four- to eightfold above that seen at normal oxygen tension ( PO2 = 150 Torr ) , sodium nitroprusside , which releases NO , suppresses this effect .
This inhibition of hypoxia-induced ET-1 expression occurs within the first hour of exposure of cells to sodium nitroprusside .
Moreover , when the endogenous constitutive levels of NO made by endothelial cells are suppressed using N-omega-nitro-L-arginine , a potent competitive inhibitor of NO synthase , the baseline levels of ET-1 produced in normoxic environments are increased three- to fourfold .
The effects of hypoxia and the NO synthase inhibitor on ET-1 expression are additive .
The regulation of ET-1 production by NO appears to be at the level of transcription .
Similar effects of NO were observed on the expression of the PDGF-B chain gene .
PDGF-B expression was suppressed by NO in a hypoxic environment and induced by N-omega-nitro-L-arginine in both normoxic and hypoxic environments .
These findings suggest that in addition to its role as a vasodilator , NO may also influence vascular tone via the regulated reciprocal production of ET-1 and PDGF-B in the vasculature .
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I Istituto Clinica Chirurgica , University of Rome La Sapienza , School of Medicine , Italy .
Surgery 113 : 691-9 ( 1993)
Abstract
BACKGROUND .
The aim of this study was to determine the correlation between hemodynamic forces and proliferation of smooth muscle cells ( SMC ) .
METHODS .
Bovine arterial SMC were seeded in a fibronectin-coated polystyrene cylinder at 5 x 10(5 ) cells/tube and allowed to reach confluence and to adhere for 48 hours .
The experimental groups were subjected to a laminar flow of 150 ml/min ( 9 dyne/cm2 ) , 100 ml/min ( 6 dyne/cm2 ) , and 50 ml/min ( 3 dyne/cm2 ) for 24 hours .
The control group was subjected to similar incubation conditions without flow .
The cells in the experiments remained attached and viable .
All experiments were performed in triplicate or more .
RESULTS .
Shear stress significantly reduced ( p < ; 0.001 ) the 24-hour incorporation of tritiated thymidine and cell proliferation .
This effect was proportional to the level of shear stress and was still evident 24 hours after flow cessation .
Results of flow cytometry confirmed a lower percentage of SMC in S phase with increasing shear stress .
Synthesis of cell-associated proteins was increased twofold ( p < ; 0.01 ) in SMC subjected to laminar flow .
SMC subjected to shear stress released a higher quantity of mitogens , including a platelet-derived growth factor ( PDGF)-like substance as detected by immunologic testing .
Fifty percent volume per volume conditioned serum-free medium from SMC subjected to shear stress increased threefold the tritiated thymidine uptake in PDGF receptor-bearing Swiss 3T3 cells as compared with conditioned serum-free medium from control SMC not subjected to shear stress and twelvefold as compared with standard control .
The release of mitogens was proportional to the level of shear stress and was still evident 24 hours after flow cessation .
The mitogenic activity was partially reduced ( 30% , p < ; 0.01 ) by an excess of monospecific anti-PDGF antibody .
CONCLUSIONS .
We conclude that ( 1 ) increasing shear stress inhibits SMC proliferation and stimulates the synthesis of cell-associated proteins and the release of mitogens and ( 2 ) decreasing shear stress facilitates proliferation of SMC .
Thus , in situations of arterial flow separation , the increased release of mitogens from SMC subjected to high shear stress and the increased proliferation rate and susceptibility to mitogens of SMC subjected to very low shear stress may generate a critical condition that predisposes to the development of atherosclerosis with early plaque formation in regions of low-flow shear stress .