Genetic deletion of ACE2 induces vascular dysfunction in C57BL/6 mice: role of nitric oxide imbalance and oxidative stress

Accumulating evidence indicates that angiotensin-converting enzyme 2 (ACE2) plays a critical role in cardiovascular homeostasis, and its altered expression is associated with major cardiac and vascular disorders. The aim of this study was to evaluate the regulation of vascular function and assess the vascular redox balance in ACE2-deficient (ACE2-/y) animals. Experiments were performed in 20-22 week-old C57BL/6 and ACE2-/y male mice. Evaluation of endothelium-dependent and -independent relaxation revealed an impairment of in vitro and in vivo vascular function in ACE2-/y mice. Drastic reduction in eNOS expression at both protein and mRNA levels, and a decrease in •NO concentrations were observed in aortas of ACE2-/y mice in comparison to controls. Consistently, these mice presented a lower plasma and urine nitrite concentration, confirming reduced •NO availability in ACE2-deficient animals. Lipid peroxidation was significantly increased and superoxide dismutase activity was decreased in aorta homogenates of ACE2-/y mice, indicating impaired antioxidant capacity. Taken together, our data indicate, that ACE2 regulates vascular function by modulating nitric oxide release and oxidative stress. In conclusion, we elucidate mechanisms by which ACE2 is involved in the maintenance of vascular homeostasis. Furthermore, these findings provide insights into the role of the renin-angiotensin system in both vascular and systemic redox balance

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction-inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension

Diastolische Dysfunktion und HFpEF bei CKD: Ein Update [Diastolic dysfunction and HFpEF in CKD: An update]

Cardiac and renal (dys)functions are closely linked. Common risk factors lead to simultaneous or sequential loss of function of both organs, and derailed compensatory mechanisms promote progression to heart and renal failure. Approximately half of the heart failure patients have preserved left ventricular pump function (HFpEF). Although chronic kidney disease (CKD) is a risk factor for the development of HFpEF, there are major knowledge gaps in the pathogenesis of HFpEF. The treatment of HFpEF with the traditional heart failure methods does not improve the prognosis in this patient population. In addition, there is little evidence in patients with advanced CKD. Cornerstones of HFpEF treatment are prevention, optimal blood pressure control, physical activity, treatment of concomitant diseases and more recently, administration of sodium-glucose transporter 2 (SGLT2) inhibitors. Mineralocorticoid receptor antagonists (MRA) and angiotensin receptor neprilysin inhibitors (ARNI) are possible adjuncts to treatment. Numerous studies are underway that could fill the remaining knowledge gaps. This review provides an update on the pathogenesis, diagnostics, and treatment of HFpEF in CKD and highlights perspectives in the treatment and research

Increase in insulin-induced relaxation of consecutive arterial segments toward the periphery: role of vascular oxidative state

Rationale: The oxidative state has been implicated in the signaling of various vasomotor functions, yet its role is less known regarding the vasomotor action of insulin. Objective: We investigated the insulin-evoked relaxations of consecutive arterial segments of different oxidative state and the role of extracellular signal-regulated kinase (ERK) pathway. Methods and Results: The oxidative state, as assessed by ortho-tyrosine was higher in thoracic aorta of rats, followed by the abdominal aorta, and was the lowest in the femoral artery. Vasomotor function of vessels of same origin was studied using a small-vessel myograph. Insulin-induced relaxations increased toward the periphery (i.e. thoracic < abdominal < femoral). Aortic banding and hydrogen peroxide/aminotriazole increased oxidative state of the thoracic aorta that was accompanied by ERK activation and decreased relaxation to insulin, and vice versa, acutely lowered oxidative state by superoxide dismutase/catalase improved relaxation. In contrast, insulin-induced relaxation of the femoral artery could be enhanced with higher, and reduced with lower oxidative state. Conclusions: Oxidative state of vessels modulates the magnitude of vasomotor responses to insulin, which appears to be mediated via the ERK signaling pathway

Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries

Rationale: Vascular wall stretch is the major stimulus for the myogenic response of small arteries to pressure. The molecular mechanisms are elusive, but recent findings suggest that G protein-coupled receptors can elicit a stretch response. Objective: Determine if angiotensin II type 1 receptors (AT1R) in vascular smooth muscle cells (VSMC) exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction. Methods and Results: We used mice deficient in AT1R signaling molecules and putative ion channel targets, namely AT1R, angiotensinogen, TRPC6 channels or several subtypes of the voltage-gated K(+) (Kv7) gene family (KCNQ3, 4 or 5). We identified a mechano-sensing mechanism in isolated mesenteric arteries and in the renal circulation that relies on coupling of the AT1R subtype a (AT1aR) to a Gq/11-protein as a critical event to accomplish the myogenic response. Arterial mechano-activation occurs after pharmacological block of AT1R, and in the absence of angiotensinogen or TRPC6 channels. Activation of AT1aR by osmotically induced membrane stretch suppresses an XE991-sensitive Kv channel current in patch-clamped VSMCs and similar concentrations of XE991 enhance mesenteric and renal myogenic tone. Although XE991-sensitive KCNQ3, 4 and 5 channels are expressed in VSMCs, XE991-sensitive K(+) current and myogenic contractions persist in arteries deficient in these channels. Conclusions: Our results provide definitive evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand-independent, mechano-activation of AT1aR. The AT1aR signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4 or 5 to enact VSMC activation and elevated vascular resistance

Physicists use mathematics to describe physical principles an mathematicians use physical phenomena to illustrate mathematical formula - Do they really mean the same?

Hydrogen sulfide (H(2)S) and NO are important gasotransmitters, but how endogenous H(2)S affects the circulatory system has remained incompletely understood. Here, we show that CTH or CSE (cystathionine γ-lyase)-produced H(2)S scavenges vascular NO and controls its endogenous levels in peripheral arteries, which contribute to blood pressure regulation. Furthermore, eNOS (endothelial NO synthase) and phospho-eNOS protein levels were unaffected, but levels of nitroxyl were low in CTH-deficient arteries, demonstrating reduced direct chemical interaction between H(2)S and NO. Pretreatment of arterial rings from CTH-deficient mice with exogenous H(2)S donor rescued the endothelial vasorelaxant response and decreased tissue NO levels. Our discovery that CTH-produced H(2)S inhibits endogenous endothelial NO bioavailability and vascular tone is novel and fundamentally important for understanding how regulation of vascular tone is tailored for endogenous H(2)S to contribute to systemic blood pressure function

Amyloid-β peptides activate α1-adrenergic cardiovascular receptors

Alzheimer disease features amyloid-beta (Abeta) peptide deposition in brain and blood vessels and is associated with hypertension. Abeta peptide can cause vasoconstriction and endothelial dysfunction. We observed that Abeta peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to alpha1-adrenergic receptor autoantibodies that we described earlier. Recently, it was shown that alpha1-adrenergic receptor could impair blood-brain flow. We hypothesized that Abeta peptides might elicit a signal transduction pathway in vascular cells, induced by alpha1-adrenergic receptor activation. Abeta (25-35) and Abeta (10-35) induced a positive chronotropic effect in the cardiac contraction assay (28.75+/-1.15 and 29.40+/-0.98 bpm), which was attenuated by alpha1-adrenergic receptor blockers (urapidil, 1.53+/-1.17 bpm; prazosin, 0.30+/-0.96 bpm). Both Abeta peptides induced an intracellular calcium release in vascular smooth muscle cells. Chronotropic activity and calcium response elicited by Abeta (25-35) were blocked with peptides corresponding to the first extracellular loop of the alpha1-adrenergic receptor. We observed an induction of extracellular-regulated kinase 1/2 phosphorylation by Abeta (25-35) in Chinese hamster ovary cells overexpressing alpha1-adrenergic receptor, vascular smooth muscle cells, and cardiomyocytes. We generated an activation-state-sensitive alpha1-adrenergic receptor antibody and visualized activation of the alpha1-adrenergic receptor by Abeta peptide. Abeta (25-35) induced vasoconstriction of mouse aortic rings and in coronary arteries in Langendorff-perfused rat hearts that resulted in decreased coronary flow. Both effects could be reversed by alpha1-adrenergic receptor blockade. Our data are relevant to the association between Alzheimer disease and hypertension. They may explain impairment of vascular responses by Abeta and could have therapeutic implications

Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients