Vascular smooth muscle contraction in hypertension

Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia, and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex-interacting systems such as the renin-angiotensin-aldosterone system, sympathetic nervous system, immune activation, and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration ([Ca2+]i), promoting actin–myosin cross-bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase, protein Kinase C and mitogen-activated protein kinase signalling, reactive oxygen species, and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and non-coding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell [Ca2+]i not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signalling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here, we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension

Characterization of large area avalanche photodiodes in X-ray and VUV-light detection

The present manuscript reviews our R+D studies on the application of large area avalanche photodiodes (LAAPDs) to the detection of X-rays and vacuum ultraviolet (VUV) light. The operational characteristics of LAAPDs manufactured by Advanced Photonix Inc. were investigated for X-ray detection at room temperature. The optimum energy resolution obtained in four LAAPDs investigated was found to be in the range 10-18% for 5.9 keV X-rays. The observed variations are associated with dark current differences between the several prototypes. LAAPDs have demonstrated high counting rate capability (up to about 10⁵/s) and applicability in diverse areas, mainly low-energy X-ray detection, where LAAPDs selected for low dark current may achieve better performance than proportional counters. LAAPDs were also investigated as VUV photosensors, presenting advantages compared to photomultiplier tubes. X-rays are often used as a reference in light measurements; this may be compromised by the non-linearity between gains measured for X-rays and VUV-light. The gain was found to be lower for X-rays than for VUV light, especially at higher bias voltages. For 5.9 keV X-rays, gain variations of 10% and 6% were measured relative to VUV light produced in argon ( ∼ 128 nm) and xenon ( ∼ 172 nm) for gains of about 200. The effect of temperature on the LAAPD performance was investigated for X-ray and VUV-light detection. Gain variations of more than -4% per oC were measured for 5.9 keV X-rays for gains above 200, while for VUV light variations are larger than -5% per oC. The energy resolution was found to improve with decreasing temperature, what is mainly attributed to dark current. The excess noise factor, another contribution to the energy resolution, was experimentally determined and found to be independent of temperature, increasing linearly with gain, from 1.8 to 2.3 for a 50-300 gain range. The LAAPD response under intense magnetic fields up to 5 Tesla was investigated. While for X-ray detection the APD response practically does not vary with the magnetic field, for 172 nm VUV light a significant amplitude reduction of more than 20% was observed

Arterial hypertension

Hypertension is a complex, multifactorial and multisystem disorder and a leading cause of morbidity and premature death globally. Major guidelines define it as systolic blood pressure > 130 mmHg and/or diastolic blood pressure > 80 mmHg. Hypertension is a very common disease with prevalence rates of about 30% in adults worldwide. The incidence of hypertension is age-related. At younger ages, hypertension is more prevalent in males than females, but this trend is reversed by age 65. Gender-related differences in hypertension may relate to cardiovascular effects of sex hormones. The underlying cause of the disease is identified in only ∼ 5% of patients (secondary hypertension), while in 95% of patients, no etiology is found (primary or essential hypertension). Multiple factors including genetics, environmental factors and interacting physiological systems contribute to the pathophysiology of hypertension. High blood pressure is a major preventable risk factor for heart failure, ischemic heart disease, chronic kidney disease, stroke and vascular dementia. The risk of hypertension-related complications and target organ admage increases as blood pressure increases. Hypertension is typically associated with vascular dysfunction, cardiovascular remodeling, renal dysfunction, and stimulation of the sympathetic nervous system. Growing evidence indicates that the immune system is also important and that activated immune cells promote inflammation, fibrosis, and target-organ damage. Common to these processes is oxidative stress, defined as an imbalance between oxidants and antioxidants in favor of the oxidants, which cause disruption of oxidation-reduction (redox) signaling and promotion of molecular and cell damage. This chapter provides a comprehensive review on hypertension and highlights some new concepts on molecular mechanisms and pathophysiological processes underlying hypertension and approaches to diagnosing and managing hypertension in the clinic

Epidermal growth factor signaling through transient receptor potential melastatin 7 cation channel regulates vascular smooth muscle cell function

Objective: Transient receptor potential (TRP) melastatin 7 (TRPM7) cation channel, a dual-function ion channel/protein kinase, regulates vascular smooth muscle cell (VSMC) Mg2+ homeostasis and mitogenic signaling. Mechanisms regulating vascular growth effects of TRPM7 are unclear, but epidermal growth factor (EGF) may be important because it is a magnesiotropic hormone involved in cellular Mg2+ regulation and VSMC proliferation. Here we sought to determine whether TRPM7 is a downstream target of EGF in VSMCs and if EGF receptor (EGFR) through TRPM7 influences VSMC function. Approach and results: Studies were performed in primary culture VSMCs from rats and humans and vascular tissue from mice deficient in TRPM7 (TRPM7+/Δkinase and TRPM7R/R). EGF increased expression and phosphorylation of TRPM7 and stimulated Mg2+ influx in VSMCs, responses that were attenuated by gefitinib (EGFR inhibitor) and NS8593 (TRPM7 inhibitor). Co-immunoprecipitation (IP) studies, proximity ligation assay (PLA) and live-cell imaging demonstrated interaction of EGFR and TRPM7, which was enhanced by EGF. PP2 (c-Src inhibitor) decreased EGF-induced TRPM7 activation and prevented EGFR–TRPM7 association. EGF-stimulated migration and proliferation of VSMCs were inhibited by gefitinib, PP2, NS8593 and PD98059 (ERK1/2 inhibitor). Phosphorylation of EGFR and ERK1/2 was reduced in VSMCs from TRPM7+/Δkinase mice, which exhibited reduced aortic wall thickness and decreased expression of PCNA and Notch 3, findings recapitulated in TRPM7R/R mice. Conclusions: We show that EGFR directly interacts with TRPM7 through c-Src-dependent processes. Functionally these phenomena regulate [Mg2+]i homeostasis, ERK1/2 signaling and VSMC function. Our findings define a novel signaling cascade linking EGF/EGFR and TRPM7, important in vascular homeostasis

SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication

COVID-19, caused by SARS-CoV-2, is a respiratory disease associated with inflammation and endotheliitis. Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS-CoV-2 may be important. Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process. Human endothelial cells were exposed to SARS-CoV-2 spike protein, S1 subunit (rS1p) and pro-inflammatory signaling and inflammatory mediators assessed. ACE2 was modulated pharmacologically and by siRNA. Endothelial cells were also exposed to SARS-CoV-2. rSP1 increased production of IL-6, MCP-1, ICAM-1 and PAI-1, and induced NFkB activation via ACE2 in endothelial cells. rS1p increased microparticle formation, a functional marker of endothelial injury. ACE2 interacting proteins involved in inflammation and RNA biology were identified in rS1p-treated cells. Neither ACE2 expression nor ACE2 enzymatic function were affected by rSP1. Endothelial cells exposed to SARS-CoV-2 virus did not exhibit viral replication. We demonstrate that rSP1 induces endothelial inflammation via ACE2 through processes that are independent of ACE2 enzymatic activity and viral replication. We define a novel role for ACE2 in COVID-19- associated endotheliitis

TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt

Hyperaldosteronism causes cardiovascular disease as well as hypomagnesemia. Mechanisms are ill-defined but dysregulation of TRPM7, a Mg2+-permeable channel/α-kinase, may be important. We examined the role of TRPM7 in aldosterone-dependent cardiovascular and renal injury by studying aldosterone-salt treated TRPM7-deficient (TRPM7+/Δkinase) mice. Plasma/tissue [Mg2+] and TRPM7 phosphorylation were reduced in vehicle-treated TRPM7+/Δkinase mice, effects recapitulated in aldosterone-salt-treated wild-type mice. Aldosterone-salt treatment exaggerated vascular dysfunction and amplified cardiovascular and renal fibrosis, with associated increased blood pressure in TRPM7+/Δkinase mice. Tissue expression of Mg2+-regulated phosphatases (PPM1A, PTEN) was downregulated and phosphorylation of Smad3, ERK1/2, and Stat1 was upregulated in aldosterone-salt TRPM7-deficient mice. Aldosterone-induced phosphorylation of pro-fibrotic signaling was increased in TRPM7+/Δkinase fibroblasts, effects ameliorated by Mg2+ supplementation. TRPM7 deficiency amplifies aldosterone-salt-induced cardiovascular remodeling and damage. We identify TRPM7 downregulation and associated hypomagnesemia as putative molecular mechanisms underlying deleterious cardiovascular and renal effects of hyperaldosteronism

Measurement of the B-s(0) ->mu(+)mu(-) branching fraction and search for B-0 -> mu(+)mu(-) with the CMS experiment

The article is the pre-print version of the final publishing paper that is available from the link below.Results are presented from a search for the rare decays B0s → m+m- and B0 →m+m- in pp collisions at at √s = 7 and 8 TeV, with data samples corresponding to integrated luminosities of 5 and 20 fb-1, respectively, collected by the CMS experiment at the LHC. An unbinned maximum-likelihood fit to the dimuon invariant mass distribution gives a branching fraction B(B0s→m+m-) = (3.0 +1.0-0.9) x 10-9, where the uncertainty includes both statistical and systematic contributions. An excess of B0s → m+m- events with respect to background is observed with a significance of 4.3 standard deviations. For the decay B0 → m+m- an upper limit of B(B0→m+m-) < 1.1 x 10-9 at the 95% confidence level is determined. Both results are in agreement with the expectations from the standard model

The Lamb shift in muonic hydrogen 1

Abstract: The long quest for a measurement of the Lamb shift in muonic hydrogen is over. Last year we measured the energy splitting (Pohl et al., Nature, 466, 213 (2010)) in mp with an experimental accuracy of 15 ppm, twice better than our proposed goal. Using current QED calculations of the fine, hyperfine, QED, and finite size contributions, we obtain a rootmean-square proton charge radius of r p = 0.841 84 (67) fm. This value is 10 times more precise, but 5 standard deviations smaller, than the 2006 CODATA value of r p . The origin of this discrepancy is not known. Our measurement, together with precise measurements of the 1S-2S transition in regular hydrogen and deuterium, gives improved values of the Rydberg constant, R ? = 10 973 731.568 16