Cardiovascular complications such as hypertension are a continuous concern in patients with autosomal dominant polycystic kidney disease (ADPKD). The PKD2 encoding for polycystin-2 is mutated in ≈15% of ADPKD patients. Here, we show that polycystin-2 is localized to the cilia of mouse and human vascular endothelial cells. We demonstrate that the normal expression level and localization of polycystin-2 to cilia is required for the endothelial cilia to sense fluid shear stress through a complex biochemical cascade, involving calcium, calmodulin, Akt/PKB, and protein kinase C. In response to fluid shear stress, mouse endothelial cells with knockdown or knockout of Pkd2 lose the ability to generate nitric oxide (NO). Consistent with mouse data, endothelial cells generated from ADPKD patients do not show polycystin-2 in the cilia and are unable to sense fluid flow. In the isolated artery, we further show that ciliary polycystin-2 responds specifically to shear stress and not to mechanical stretch, a pressurized biomechanical force that involves purinergic receptor activation. We propose a new role for polycystin-2 in transmitting extracellular shear stress to intracellular NO biosynthesis. Thus, aberrant expression or localization of polycystin-2 to cilia could promote high blood pressure because of inability to synthesize NO in response to an increase in shear stress (blood flow).

Efficient detoxification of bile acids is necessary to avoid pathological conditions such as cholestatic liver damage and colon cancer. The orphan nuclear receptors PXR and CAR have been proposed to play an important role in the detoxification of xeno-and endo-biotics by regulating the expression of detoxifying enzymes and transporters. In this report, we showed that the combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex-sensitive manner. A regimen of lithocholic acid treatment, which was tolerated by wild-type and PXR null mice, caused a marked accumulation of serum bile acids and histological liver damage as well as an increased hepatic lipid deposition in double knockout males. The increased sensitivity in males was associated with genotype-specific suppression of bile acid transporters and loss of bile acid-mediated downregulation of small heterodimer partner, whereas the transporter suppression was modest or absent in females. The double knockout mice also exhibited gene-and tissue-specific dysregulation of PXR and CAR target genes in response to PXR and CAR agonists. In conclusion, although the cross-regulation of target genes by PXR and CAR has been proposed, the current study represents in vivo evidence of the combined loss of both receptors causing a unique pattern of gene regulation that can be translated into physiological events such as sensitivity to toxic bile acids. (HEPATOLOGY 2005;41:168 -176.)

Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 g·kg Ϫ1 ·day Ϫ1 ) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E 2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E 2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E 2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E 2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E 2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E 2's mechanisms may lead to novel RV-directed therapies.sugen/hypoxia; fibrosis; apoptosis; endothelial nitric oxide synthase; autophagy PULMONARY ARTERIAL HYPERTENSION (PAH) is a sexually dimorphic disease with a female-to-male ratio of up to 4:1 (3). Despite availability of 14 Food and Drug Administrationapproved medications, PAH remains a devastating, progressive, and incurable disease, evidenced by the disappointing 3-yr survival rate of only 55% (22). Even though both female sex and right ventricular (RV) function are major determinants of survival in PAH (5, 22, 23), no RV-or sex steroid-directed therapies exist. This is of importance, since women, despite being more prone to PAH development, exhibit better survival than male patients, a phenomenon attributed, at least in part, to better RV function in women (22,23,26,34,62).We and others demonstrated that the female sex hormone 17␤-estradiol (E 2 ) exerts protective effects on RV function in experimental PAH (11,36,37,60), findings that support observations made in healthy postmenopausal hormone replacement therapy users, where circulating E 2 levels correlate with better RV ejection fraction (61). Given the superior RV function of female PAH patients (23, 26), the exquisite sensitivity of the RV to increases in afterload (19), and the recent observation that exercise and physical activity...