Trends in Pharmacological Sciences
Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces
Section snippets
Nitric oxide
In endothelial cells, NO is generated by a constitutive, Ca2+–calmodulin-dependent, NO synthase (eNOS) [1]. Generally, NO induces smooth muscle relaxation by activating soluble guanylyl cyclase. This increases intracellular concentrations of cyclic guanosine monophosphate (cGMP), which, in turn, activates the G kinase and reduces the intracellular concentration of Ca2+ ([Ca2+]i) in smooth muscle cells and results in relaxation. Application of a receptor-dependent agonist to endothelial cells is
PGI2
A key enzyme in the synthesis of prostanoids is prostaglandin H (PGH) synthase, also known as cyclooxygenase (COX). Under normal physiological conditions COX-dependent vasodilators regulate vascular tone. However, COX-dependent vasoconstriction, which is mediated by thromboxane and/or its immediate precursor PGH2, predominates in some vascular pathologies. Two isoforms of COX have been identified, COX-1 and COX-2; both catalyze the same reaction but they have distinct pharmacological profiles
EDHF
In addition to NO and PGI2, endothelial cells release an endothelium-derived vasodilator autacoid that induces relaxation by hyperpolarizing vascular smooth muscle cells. The identity of this so-called EDHF is controversial, probably because there is more than one type of EDHF. Of the candidate EDHFs proposed to date, most research has focused on mechanisms that involve: (1) generation of epoxyeicosatrienoic acids (EETs) by a cytochrome P450 epoxygenase in endothelial cells; either the EETs act
Reactive oxygen species
Over the past few years a link between increased vascular oxidative stress and cardiovascular disease has been established. However, generation of O2− and other ROS, including hydrogen peroxide (H2O2), in the vasculature occurs under normal physiological conditions and is not restricted to pathophysiology. Although arteriolar smooth muscle cells are mechanosensitive and constrict in response to elevations in transmural pressure, ROS are not generated solely in smooth muscle cells. Depending on
Endothelin 1
ET-1 is a 21-amino-acid peptide that is synthesized in several cell types, including the vascular endothelium. Production and release of ET-1 is stimulated by many hormonal and metabolic factors, as well as hypoxia and, most importantly, shear stress and cyclic stretch. Once released, ET-1 binds to ETA receptors on vascular smooth muscle cells, which mediate vasoconstriction, and ETB receptors on endothelium, which are linked to the formation of NO and PGI2. Several lines of evidence indicate
Endothelial dysfunction
Cardiovascular disorders, such as atherosclerosis, coronary artery disease, diabetes and some forms of hypertension, are associated with an attenuated vasodilator response to acetylcholine and/or an increase in blood flow. This attenuated response, referred to as ‘endothelial dysfunction’, is thought to reflect a defect that results in reduced generation of NO and/or its enhanced scavenging by ROS generated within either endothelial cells or underlying smooth muscle cells of the vasculature.
How does the endothelium sense mechanical stimuli?
Initially, the first step in this process was thought to be activation of a mechanoreceptor that senses changes in membrane tension on the luminal surface of the endothelial cell. Endothelial cells contain mechanosensitive ion channels that respond primarily to changes in membrane tension and renders them appropriate transducers for forces derived from osmotic or hydraulic gradients and shear stress.
The open probability of these, mainly cation-selective, channels might be modulated by membrane
Acknowledgements
Experimental work performed in our laboratory was supported by the Deutsche Forschungsgemeinschaft (SFB 553, B1).
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