Research line

Endothelium is recognized as an important modulator in vascular homeostasis, mainly due to its ability to release vasoactive molecules like nitric oxide (NO) which plays a critical role in the regulation of vascular tone and maintenance of vascular integrity. NO is generated in endothelial cells by the activity of the endothelial nitric oxide synthase (eNOS) and diffuses to the surrounding vascular smooth muscle, leading to vasorelaxation by stimulation of the guanylate cyclase pathway and the consequent generation of cGMP. The endothelium-dependent vasodilation mediated by NO depends critically on availability of the substrate L-arginine which is uptaked by the cationic amino acid transporter systems (CATs). Intracellular L-arginine may be metabolized by a second pathway that involves the activity of arginases I (ARGI) and II (ARGII), which produces L-ornithine and urea. It has been postulated that a competition of ARG and NOS for the common substrate L-arginine could lead to endothelial dysfunction in important diseases such as diabetes, hypertension, pulmonary hypertension, erectile dysfunction and aging. Recent research provides evidences that the small G protein RhoA plays an important role in regulation of various cellular functions in the vasculature. Rho-kinase/ROCK2, one of the downstream effectors of RhoA, is a serine/threonine kinase that is activated when it binds to the active GTP-bound form of RhoA. With regard to its role in the regulation of NO production, recent studies using Rho-kinase inhibitors demonstrated that Rho-kinase down-regulates eNOS expression and enzyme activity. Nonetheless, the physiological and biochemical relevance of eNOS regulation by RhoA and Rho-kinase has not yet been analyzed.

In some pregnancy related diseases such as Intrauterine Growth Restriction (IUGR) there is a reduction in oxygen concentration in the fetal circulation which can cause alterations in fetal development. The fetal adaptation to this intrauterine stress may lead to ‘Fetal Programming' of vascular dysfunction mainly due to lower NO bioavailability in placenta vascular endothelial cells.