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 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.

Abstract-Current mlcroscoplc methods to view renal mlcrovasculature reveal only a very hmlted portion of the total renal volume Identlficatlon of connectlvlty for postglomerular vessels m the cortex and the medulla durmg functional states related to changes m sodium excretion will help better to understand the couplmg of renal vasculature to tubular function The purpose of this study was to investigate the posslblhty of vlsuahzmg the contmmty of pre-and postglomerular vasculature using three-dlmennonal micro-computed tomography ( micro-CT) Kidneys from normal rats were perfusion fixed m situ at physlologlcal pressure, filled with latex mlcrofil contammg lead chromate, and embedded m plastic The micro-CT scans of the intact kidneys were carned out on a rotating stage lllummated either by a synchrotron x-ray source or a conventional x-ray spectroscopy tube Images were reconstructed by a filtered backproJection algorithm and volume-rendering techniques were utilized to display the vasculature The reconstructed images clearly showed the large dlstrlbutlon vessels and the venous dramage of the kidneys, while pre-and postglomerular vessels and their vascular connections throughout the kidney were displayed m great detail Efferent artenoles showed the charactenstlcs of then perltubular capillary beds m the cortical and medullary regions The vascular volume of the cortex was 27%, the outer stripe of the outer medulla 18%, the mner stripe of the outer medulla 30%, and the mner medulla 18% In conclusion, micro-CT 1s a promlsmg method to evaluate renal vascular architecture relative to phynologcal and pathological alterations (Hypertension.

Abstract-Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-␤ receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-␤ receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-␤ type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-␤-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-␤ 1 administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology. Key Words: endothelial cells Ⅲ hypertension Ⅲ TGF-␤ receptors Ⅲ aging Ⅲ endoglin C ardiovascular repair mechanisms become progressively impaired with age, and advanced age is itself a significant risk factor for cardiovascular disease. 1 Defects in age-associated remodeling of the vascular wall are, in part, attributable to the declining of endothelial function. 2,3 Thus, vascular processes such as angiogenesis, nutrient trafficking, vascular repair, and homeostasis are impaired because of attenuation of endothelial cell (EC) proliferation, migration, or dilator responses. EC proliferation diminishes with age, entering in an irreversible senescent state. 4 Senescent cells undergo growth arrest in the G 1 phase and a change in morphology and metabolism. Some of the senescence-associated changes include cellular enlargement, altered response to growth factors such as transforming growth factor (TGF)-␤ 1 , and expression of senescence-associated ␤-galactosidase (SA-␤-gal). 5 Also, alterations in the expression and/or activity of the endothelial nitric oxide synthase (eNOS) are critical for the attenuation of the endothelium-dependent dilatory responses with age. 6,7 Unfortunately, most of the functional and gene expression changes associated with...