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Gender pharmacology: focus on endothelial dysfunction  

Gender pharmacology: focus on endothelial dysfunction

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in western countries. But they are also a classical example of disease where sex/gender differences have been described. A significant body of evidence suggests that CVDs are less prevalent in women than men until midlife, and the female advantage has been attributed to estrogens, which are lost with menopause. On the contrary, the incidence of CV accidents is higher in women than in men after menopause.

          Since the earliest event in the onset of atherosclerosis and CVDs is endothelial dysfunction (ED),  many in vitro studies have been focused on endothelial cells (ECs). These cells synthesize a series of substances with a defensive role against the endothelium damage, and among these molecules, nitric oxide (NO) is the most effective protective agent. Once produced by ECs, NO diffuses to the neighbouring smooth muscle cells and to circulating platelets, thus exerting positive vasodilator and anti-aggregant effects.

          NO is produced by ECs through the action of the specific enzyme endothelial NO synthase (eNOS). The activity of eNOS must be very tightly controlled to guarantee an appropriate NO formation, necessary for the correct functioning and integrity of the cardiovascular system. As a matter of fact, the primary event in ED is a loss in the eNOS activity - with a consequent reduced release of NO - coupled with an increase in Reactive Oxygen Species (ROS) in the vascular wall.

 

          In order to have a better insight in the possible differences between male and female EC behaviour, we thought of interest to compare the expression and function of eNOS in primary cultures of human male and female ECs (HUVECs, abbreviated as M-ECs and F-ECs, respectively). We found  that F-ECs constitutively  express an higher amount of eNOS both at mRNA and protein level. Moreover, F-ECs possess greater migratory and 3D-spheroid sprouting capabilities in comparison to M-ECs. The increased migratory and angiogenic capabilities observed in F-ECs are counteracted by the pharmacological inhibition and silencing of eNOS. At variance,  M-EC motility and sprouting appear to be eNOS-independent.

          These results suggest that the constitutive higher expression of eNOS observed in F-ECs might contribute to the protection against CVDs showed by the young female population.

 

          We are carrying out further studies in ECs at different ages to determine if the differences we observed in “baby” EC are preserved during lifetime in both  adulthood and  ageing. Furthermore, we are investigating the role of estrogen on male and female eNOS function and expression, and more in general on EC physiological functions. The knowledge derived from these studies could help to optimize sex/gender-specific therapy and, finally, improve clinical outcomes in patients with CVDs.

 

Human primary ECs obtained from umbilical cords (HUVECs) are routinely available in our lab. Tests for evaluating in vitro angiogenesis – i.e. proliferation, 2D chemotaxis and migration, 3D sprouting assay - are usually running.

 

Composizione del gruppo e contatti:

Lucia Vicentini – lucia.vicentini@unimi.it

Maria Grazia Cattaneo – mgrazia.cattaneo@unimi.it

 

Ubicazione:

Via Vanvitelli, 32

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