17beta-estradiol inhibits apoptosis of endothelial cells.

Endothelial cells provide an antithrombotic and anti-inflammatory barrier for the normal vessel wall. Dysfunction of endothelial cells has been shown to promote atherosclerosis, and normalization of previously dysfunctional endothelial cells can inhibit the genesis of atheroma. In normal arteries, endothelial cells are remarkably quiescent. Acceleration of the turnover rate of endothelial cells can lead to their dysfunction. Apoptosis is a physiological process that contributes to vessel homeostasis, by eliminating damaged cells from the vessel wall. However, increased endothelial cell turnover mediated through accelerated apoptosis may alter the function of the endothelium and therefore, promote atherosclerosis. Apoptotic endothelial cells can be detected on the luminal surface of atherosclerotic coronary vessels, but not in normal vessels. This finding links endothelial cell apoptosis and the process of atherosclerosis, although a causative role for apoptosis in this process remains hypothetical. Estrogen metabolites have been shown to be among the most potent anti-atherogenic agents available to date for post-menopausal women. The mechanism of estrogen's protective effect is currently incompletely characterized. Here we show that 17beta-estradiol, a key estrogen metabolite, inhibits apoptosis in cultured endothelial cells. Our data support the hypothesis that 17beta-estradiol's anti-apoptotic effect may be mediated via improved endothelial cell interaction with the substratum, increased tyrosine phosphorylation of pp125 focal adhesion kinase, and a subsequent reduction in programmed cell death of endothelial cells. Inhibition of apoptosis by estrogens may account for some of the anti-atherogenic properties of these compounds.

Growth factor receptors, phospholipases, phospholipid kinases and actin reorganization.

Upon binding to their ligand, several growth factor receptors that contain a tyrosine kinase within their cytoplasmic domain [receptor tyrosine kinases (RTKs)] induce a substantial reorganization of the actin cytoskeleton. This change in actin superstructure is necessary to produce multiple motile responses within the target cells. RTKs catalyse the clustering of effector proteins within functional units underneath the plasma membrane. Upon reaching a critical mass, RTK-effector units send out signals through the metabolism of membrane phospholipids and other second messenger molecules that regulate the interaction of actin with its satellite regulatory molecules. Several actin binding proteins interact transiently with small clusters of membrane inositol phospholipids in vitro (4 to 5 phospholipid molecules per actin binding protein). Such transient complex formation can either down-regulate or up-regulate the interaction of regulatory proteins with actin. The phospholipids involved in the surface catalytic control of the actin cytoskeleton are metabolically very active and abundant in cells, and are therefore poised to mediate reactions linking signal transduction molecules to the reorganization of the actin cytoskeleton upon cell activation.

Decreased coronary flow reserve after transient myocardial ischemia in dogs.

The effect of a transient (15 min) period of regional ischemia on coronary flow reserve in the postischemic myocardium was studied in 24 open chest dogs. Coronary flow was measured with electromagnetic flow probes, and flow reserve was determined during reactive hyperemia after 30 s coronary occlusions and during intracoronary infusions of adenosine. Measures of flow reserve after 15 min of ischemia were made after coronary flow returned to basal levels and flow reserve was then monitored for 1 h. All measures of coronary flow reserve were significantly reduced after transient ischemia: peak flows during reactive hyperemia and intracoronary adenosine infusions decreased by 20 and 24%, respectively, the peak/basal flow ratio by 16% and the repayment/debt ratio by 54%; minimal coronary vascular resistance during reactive hyperemia and intracoronary adenosine increased by 29 and 33%, respectively. Abnormal flow reserve was present for at least 1 h. No changes in flow reserve were detected in control animals over the same time period. Thus, a transient period of myocardial ischemia significantly decreases coronary flow reserve for a prolonged period of time. This "vascular stunning" must be considered when flow reserve is used to assess the functional significance of a coronary stenosis and could be the cause of variable exercise tolerance in patients with angina pectoris.