Analysis of Vascular Cell Response to Hypertension Induced by Pressure Loading and Its Application as a Tool for Exploring Pharmacological Modes of Action.

Abstract

Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression is induced by interleukin-1β (IL-1β) stimulation in vascular smooth muscle cells (VSMCs), resulting in the production of nitric oxide and prostaglandins such as PGI2. The expression of iNOS and COX-2 in cultured VSMCs isolated from 6-7-week-old stroke-prone spontaneously hypertensive rats (SHRSP) is significantly lower than in cells of normotensive Wistar Kyoto rats (WKY). These reductions are also found in cells exposed to pulsatile atmospheric pressure between 80-160 mmHg at a rate of 4 cycles/min, which simulates systolic hypertension. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, potentiates IL-1β-induced iNOS and COX-2 expression in VSMCs isolated from WKY, but not those from SHRSP. In response to endothelial injury at a local site, iNOS and COX-2 induction in VSMCs may function primarily as a defensive and compensatory mechanism for endothelial dysfunction by preventing the development of pathological conditions. Thus, in certain pathological conditions associated with hypertension, vascular walls with reduced iNOS and COX-2 expression may aggravate or initiate further vascular injury. In this situation, DHA may contribute to maintaining homeostasis in VSMCs by potentiating iNOS and COX-2 expression. Using cells isolated from a genetic pathological animal model alongside cells exposed to experimental pathological conditions can be an effective tool for the analysis of cell response to hypertension and exploring pharmacological modes of action in vitro.