Perturbations in paracrine control of the circulation: role of the endothelial-derived vasomediators, endothelin-1 and nitric oxide

Abstract

Central to the control of vascular resistance in the systemic and pulmonary circulation and at the solid organ level is the function of the endothelial-derived vasomediators, endothelin-1 (ET-1) and nitric oxide. Regulation of steady-state levels of ET-1 and endothelial nitric oxide synthase (eNOS) mRNAs represents an early and influential step in their biosynthesis and is highly responsive to exogenous stimuli. ET-1 is expressed from a rapidly inducible promoter to generate a highly labile mRNA. Conversely, the eNOS promoter generates a constitutive level of a very stable mRNA and utilizes posttranscriptional mechanisms to modulate mRNA expression. The response of these genes in models of cellular activation commonly reflects a reciprocal pattern of regulation, namely, transcriptional induction of ET-1 and destabilization of the eNOS mRNA. Elucidating the mechanisms influencing ET-1 and eNOS mRNA is providing novel insight into endothelial gene regulation and providing opportunities for future therapeutic strategies.