Endoglin is a membrane glycoprotein that plays an important role in cardiovascular development and angiogenesis. We examined the role of endoglin in the control of vascular tone by measuring nitric oxide (NO)-dependent vasodilation in haploinsufficient mice (Eng+/-) and their Eng+/+ littermates. The vasodilatory effect of acetylcholine, bradykinin, and sodium nitroprusside was assessed in anesthetized mice; in isolated, perfused hindlimbs; and in aortic rings. The substantial hypotensive and vasodilatory response induced by acetylcholine and bradykinin in Eng+/+ was markedly reduced in Eng+/- mice. Both kinds of animals had similar responses to sodium nitroprusside, suggesting that the deficient vasodilatory effect is not due to a NO response impairment. Urinary and plasma concentrations of nitrites, a NO metabolite, were lower in Eng+/- than in Eng+/+ mice. The levels of endothelial nitric oxide synthase (eNOS) in kidneys and femoral arteries were about half in Eng+/- than in Eng+/+ mice and were also reduced in primary cultures of aortic endothelial cells from Eng+/- compared with those from Eng+/+ mice. Furthermore, overexpression or suppression of endoglin in cultured cells induced a marked increase or decrease in the protein levels of eNOS, respectively. Thus, our results in vivo and in vitro demonstrate a relationship between endoglin and NO-dependent vasodilation mediated by the regulation of eNOS expression.

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.

Although vascular development is normal in Eng(+/-) mice, angiogenic abnormalities were observed in the adult mice and their isolated endothelial cells. These results suggest that a normal level of endoglin is required for full angiogenic activity.

Background-Telomere shortening has been related to vascular dysfunction and hypertension. In the present study, we analyzed the influence of telomerase deficiency and telomere shortening on arterial pressure (AP). Methods and Results-AP was evaluated in 6-month-old mice lacking the RNA component of the telomerase (terc Ϫ/Ϫ ) at the first generation and third generation (G3). First generation and G3 mice showed higher AP than wild-type (WT) mice. To analyze the mechanisms involved, mean AP and vascular resistance in response to vasoactive substances were measured in G3 and WT mice. These mice showed similar responses to acetylcholine, N G -nitro-L-arginine methyl ester, angiotensin II, and losartan administration. Mean AP did not increase after endothelin-1 (ET-1) administration in G3 mice, but it did in WT animals. Bosentan treatment decreased mean AP only in G3 mice. Serum and urine concentrations of ET-1 were higher in terc Ϫ/Ϫ than in WT mice. Endothelin-converting enzyme (ECE-1) mRNA expression was higher in terc Ϫ/Ϫ animals than in the WT group. FR901533, an ECE antagonist, decreased blood pressure in conscious G3 mice. Studies in mouse embryonic fibroblasts from G3 mice suggest that ECE-1 overexpression could be mediated by reactive oxygen species in an AP-1-dependent mechanism, in which some kinases such as PI3-kinase, Akt, erk1/2, and Jun Kinase could be involved. An increased activity of nicotinamide adenine dinucleotide phosphate oxidase seems to be the main source of reactive oxygen species. Conclusions-Mice lacking telomerase activity show hypertension as a result of an increase in plasma ET-1 levels, which is a consequence of ECE-1 overexpression. A direct link between telomerase activity and hypertension is reported.