Homochiral vs. heterochiral preference in chiral self-recognition of cyclic diols.

The structure and clustering propensity of a chiral derivative of cis-1,2-cyclohexanediol, namely, 1-phenyl-cis-1,2-cyclohexanediol (cis-PCD), has been studied under supersonic expansion conditions by combining laser spectroscopy with quantum chemistry calculations. The presence of the phenyl substituent induces conformational locking relative to cis-1,2-cyclohexanediol (cis-CD), and only one conformer of the bare molecule is observed by both Raman and IR-UV double resonance spectroscopy. The homochiral preference inferred for the dimer formation at low enough temperature is in line with the formation of a conglomerate in the solid state. The change in clustering propensity in cis-PCD relative to trans-1,2-cyclohexanediol (trans-CD), which shows heterochiral preference, is explained by the presence of the phenyl substituent rather than the effect of cis-trans isomerism. Indeed the transiently chiral cis-CD also forms preferentially heterodimers, whose structure is very close to that of the corresponding trans-CD dimer.

Conformer-Selective Photoelectron Circular Dichroism.

Conformational flexibility and chirality both play a key role in molecular recognition. It is therefore very useful to develop spectroscopic methods that simultaneously probe both properties. It has been theoretically predicted that photoelectron circular dichroism (PECD) should be very sensitive to conformational isomerism. However, experimental proof has been less forthcoming and only exists for a very few favorable cases. Here, we present a new PECD scheme based on resonance-enhanced two-photon ionization (RE2PI) using UV/Vis nanosecond laser excitations. The spectral resolution obtained thereby guarantees conformer-selectivity by inducing resonant conformer-specific ππ* S1←S0 transitions. We apply this experimental scheme to the study of chiral 1-indanol, which exists in two conformers linked by a ring inversion and defined by the position of the hydroxyl group, namely axial and equatorial. We show that the PECD of the equatorial and axial forms considerably differ in sign, magnitude and shape. We also discuss the influence of the total ionization energy, vibronic excitation of intermediate and final states, and relative polarization of the excitation and ionization lasers. Conformer-specificity adds a new dimension to the applications of PECD in analytical chemistry addressing now the general case of floppy systems.

Induced photoelectron circular dichroism onto an achiral chromophore.

An achiral chromophore can acquire a chiral spectroscopic signature when interacting with a chiral environment. This so-called induced chirality is documented in electronic or vibrational circular dichroism, which arises from the coupling between electric and magnetic transition dipoles. Here, we demonstrate that a chiroptical response is also induced within the electric dipole approximation by observing the asymmetric scattering of a photoelectron ejected from an achiral chromophore in interaction with a chiral host. In a phenol-methyloxirane complex, removing an electron from an achiral aromatic π orbital localised on the phenol moiety results in an intense and opposite photoelectron circular dichroism (PECD) for the two enantiomeric complexes with (R) and (S) methyloxirane, evidencing the long-range effect (~5 Å) of the scattering chiral potential. This induced chirality has important structural and analytical implications, discussed here in the context of growing interest in laser-based PECD, for in situ, real time enantiomer determination.

The first HyDRA challenge for computational vibrational spectroscopy.

Vibrational spectroscopy in supersonic jet expansions is a powerful tool to assess molecular aggregates in close to ideal conditions for the benchmarking of quantum chemical approaches. The low temperatures achieved as well as the absence of environment effects allow for a direct comparison between computed and experimental spectra. This provides potential benchmarking data which can be revisited to hone different computational techniques, and it allows for the critical analysis of procedures under the setting of a blind challenge. In the latter case, the final result is unknown to modellers, providing an unbiased testing opportunity for quantum chemical models. In this work, we present the spectroscopic and computational results for the first HyDRA blind challenge. The latter deals with the prediction of water donor stretching vibrations in monohydrates of organic molecules. This edition features a test set of 10 systems. Experimental water donor OH vibrational wavenumbers for the vacuum-isolated monohydrates of formaldehyde, tetrahydrofuran, pyridine, tetrahydrothiophene, trifluoroethanol, methyl lactate, dimethylimidazolidinone, cyclooctanone, trifluoroacetophenone and 1-phenylcyclohexane-cis-1,2-diol are provided. The results of the challenge show promising predictive properties in both purely quantum mechanical approaches as well as regression and other machine learning strategies.

Smooth muscle mineralocorticoid receptor as an epigenetic regulator of vascular ageing.

AIMS: Vascular stiffness increases with age and independently predicts cardiovascular disease risk. Epigenetic changes, including histone modifications, accumulate with age but the global pattern has not been elucidated nor are the regulators known. Smooth muscle cell-mineralocorticoid receptor (SMC-MR) contributes to vascular stiffness in ageing mice. Thus, we investigated the regulatory role of SMC-MR in vascular epigenetics and stiffness. METHODS AND RESULTS: Mass spectrometry-based proteomic profiling of all histone modifications completely distinguished 3 from 12-month-old mouse aortas. Histone-H3 lysine-27 (H3K27) methylation (me) significantly decreased in ageing vessels and this was attenuated in SMC-MR-KO littermates. Immunoblotting revealed less H3K27-specific methyltransferase EZH2 with age in MR-intact but not SMC-MR-KO vessels. These ageing changes were examined in primary human aortic (HA)SMC from adult vs. aged donors. MR, H3K27 acetylation (ac), and stiffness gene (connective tissue growth factor, integrin-α5) expression significantly increased, while H3K27me and EZH2 decreased, with age. MR inhibition reversed these ageing changes in HASMC and the decline in stiffness genes was prevented by EZH2 blockade. Atomic force microscopy revealed that MR antagonism decreased intrinsic stiffness and the probability of fibronectin adhesion of aged HASMC. Conversely, ageing induction in young HASMC with H2O2; increased MR, decreased EZH2, enriched H3K27ac and MR at stiffness gene promoters by chromatin immunoprecipitation, and increased stiffness gene expression. In 12-month-old mice, MR antagonism increased aortic EZH2 and H3K27 methylation, increased EZH2 recruitment and decreased H3K27ac at stiffness genes promoters, and prevented ageing-induced vascular stiffness and fibrosis. Finally, in human aortic tissue, age positively correlated with MR and stiffness gene expression and negatively correlated with H3K27me3 while MR and EZH2 are negatively correlated. CONCLUSION: These data support a novel vascular ageing model with rising MR in human SMC suppressing EZH2 expression thereby decreasing H3K27me, promoting MR recruitment and H3K27ac at stiffness gene promoters to induce vascular stiffness and suggests new targets for ameliorating ageing-associated vascular disease.

Photoelectron Circular Dichroism as a Signature of Subtle Conformational Changes: The Case of Ring Inversion in 1-Indanol.

Chirality plays a fundamental role in the molecular recognition processes. Molecular flexibility is also crucial in molecular recognition, allowing the interacting molecules to adjust their structures and hence optimize the interaction. Methods probing simultaneously chirality and molecular conformation are therefore crucially needed. Taking advantage of a possible control in the gas phase of the conformational distribution between the equatorial and axial conformers resulting from a ring inversion in jet-cooled 1-indanol, we demonstrate here the sensitivity of valence-shell photoelectron circular dichroism (PECD) to both chirality and subtle conformational changes, in a case where the photoelectron spectra of the two conformers are identical. For the highest occupied orbital, we observe a dramatic inversion of the PECD-induced photoelectron asymmetries, while the photoionization cross-section and usual anisotropy (ß) parameter are completely insensitive to conformational isomerism. Such a sensitivity is a major asset for the ongoing developments of PECD-based techniques as a sensitive chiral (bio)chemical analytical tool in the gas phase.

NR1D1 regulation by Ran GTPase via miR4472 identifies an essential vulnerability linked to aneuploidy in ovarian cancer.

While aneuploidy is a main enabling characteristic of cancers, it also creates specific vulnerabilities. Here we demonstrate that Ran inhibition targets epithelial ovarian cancer (EOC) survival through its characteristic aneuploidy. We show that induction of aneuploidy in rare diploid EOC cell lines or normal cells renders them highly dependent on Ran. We also establish an inverse correlation between Ran and the tumor suppressor NR1D1 and reveal the critical role of Ran/NR1D1 axis in aneuploidy-associated endogenous DNA damage repair. Mechanistically, we show that Ran, through the maturation of miR4472, destabilizes the mRNA of NR1D1 impacting several DNA repair pathways. We showed that NR1D1 interacts with both PARP1 and BRCA1 leading to the inhibition of DNA repair. Concordantly, loss of Ran was associated with NR1D1 induction, accumulation of DNA damages, and lethality of aneuploid EOC cells. Our findings suggest a synthetic lethal strategy targeting aneuploid cells based on their dependency to Ran.

Microdissected Tissue vs Tissue Slices-A Comparative Study of Tumor Explant Models Cultured On-Chip and Off-Chip.

Predicting patient responses to anticancer drugs is a major challenge both at the drug development stage and during cancer treatment. Tumor explant culture platforms (TECPs) preserve the native tissue architecture and are well-suited for drug response assays. However, tissue longevity in these models is relatively low. Several methodologies have been developed to address this issue, although no study has compared their efficacy in a controlled fashion. We investigated the effect of two variables in TECPs, specifically, the tissue size and culture vessel on tissue survival using micro-dissected tumor tissue (MDT) and tissue slices which were cultured in microfluidic chips and plastic well plates. Tumor models were produced from ovarian and prostate cancer cell line xenografts and were matched in terms of the specimen, total volume of tissue, and respective volume of medium in each culture system. We examined morphology, viability, and hypoxia in the various tumor models. Our observations suggest that the viability and proliferative capacity of MDTs were not affected during the time course of the experiments. In contrast, tissue slices had reduced proliferation and showed increased cell death and hypoxia under both culture conditions. Tissue slices cultured in microfluidic devices had a lower degree of hypoxia compared to those in 96-well plates. Globally, our results show that tissue slices have lower survival rates compared to MDTs due to inherent diffusion limitations, and that microfluidic devices may decrease hypoxia in tumor models.

Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor.

Aging is associated with heart and vascular dysfunction that contributes to cardiovascular disease (CVD) risk. Clinical data support a sexual dimorphism in the time course of aging-associated CVD. However, the mechanisms driving sex differences in cardiovascular aging and whether they can be modeled in mice have not been explored. Mineralocorticoid receptors (MRs) regulate blood pressure, and we previously demonstrated in male mice that MR expression increases in aging mouse vessels and smooth muscle cell-specific MR deletion (SMC-MR-KO) protects from cardiovascular aging. This study characterizes sex differences in murine cardiovascular aging and the associated sex-specific role of SMC-MR. Aortic stiffness, measured by pulse wave velocity, increased from 3 to 12 mo of age in males but not until 18 mo in females. The timing of the rise in aortic stiffening correlated with the timing of increased aortic MR expression, and aortic stiffness did not increase with age in SMC-MR-KO mice of both sexes. Vascular fibrosis increased at 12 mo in males and later at 18 mo in females; however, fibrosis was attenuated by SMC-MR-KO in males only. In resistance vessels, angiotensin type 1 receptor (AT1R)-mediated vasoconstriction also increased at 12 mo in males and 18 mo in females. ANG II-induced vasoconstriction was decreased in SMC-MR-KO specifically in males in association with decreased AT1R expression. Cardiac systolic function declined in males and females by 18 mo of age, which was prevented by SMC-MR-KO specifically in females. Cardiac perivascular fibrosis increased with age in both sexes accompanied by sex-specific changes in the expression levels of MR-regulated profibrotic genes.NEW & NOTEWORTHY These data demonstrate that the delayed and steeper decline in cardiovascular function observed in aging females can be modeled in aging mice. Moreover, the mechanisms driving vascular and cardiac aging phenotypes are distinct between males and females. Mineralocorticoid receptors in smooth muscle cells play a significant role in cardiovascular aging in both sexes; however, they do so by distinct mechanisms. Overall, these findings suggest that sex-specific therapies may be necessary to retard the aging process and improve cardiovascular disease outcomes in the aging population.

Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease.

Cancer cell lines are amongst the most important pre-clinical models. In the context of epithelial ovarian cancer, a highly heterogeneous disease with diverse subtypes, it is paramount to study a wide panel of models in order to draw a representative picture of the disease. As this lethal gynaecological malignancy has seen little improvement in overall survival in the last decade, it is all the more pressing to support future research with robust and diverse study models. Here, we describe ten novel spontaneously immortalized patient-derived ovarian cancer cell lines, detailing their respective mutational profiles and gene/biomarker expression patterns, as well as their in vitro and in vivo growth characteristics. Eight of the cell lines were classified as high-grade serous, while two were determined to be of the rarer mucinous and clear cell subtypes, respectively. Each of the ten cell lines presents a panel of characteristics reflective of diverse clinically relevant phenomena, including chemotherapeutic resistance, metastatic potential, and subtype-associated mutations and gene/protein expression profiles. Importantly, four cell lines formed subcutaneous tumors in mice, a key characteristic for pre-clinical drug testing. Our work thus contributes significantly to the available models for the study of ovarian cancer, supplying additional tools to better understand this complex disease.

Site-fidelity and spatial movements of western North Pacific gray whales on their summer range off Sakhalin, Russia.

The Western North-Pacific (WNP) gray whale feeding grounds are off the northeastern coast of Sakhalin Island, Russia and is comprised of a nearshore and offshore component that can be distinguished by both depth and location. Spatial movements of gray whales within their foraging grounds were examined based on 13 years of opportunistic vessel and shore-based photo-identification surveys. Site fidelity was assessed by examining annual return and resighting rates. Lagged Identification Rates (LIR) analyses were conducted to estimate the residency and transitional movement patterns within the two components of their feeding grounds. In total 243 individuals were identified from 2002-2014, among these were 94 calves. The annual return rate over the period 2002-2014 was 72%, excluding 35 calves only seen one year. Approximately 20% of the individuals identified from 2002-2010 were seen every year after their initial sighting (including eight individuals that returned for 13 consecutive years). The majority (239) of the WNP whales were observed in the nearshore area while only half (122) were found in the deeper offshore area. Within a foraging season, there was a significantly higher probability of gray whales moving from the nearshore to the offshore area. No mother-calf pairs, calves or yearlings were observed in the offshore area, which was increasingly used by mature animals. The annual return rates, and population growth rates that are primarily a result of calf production with little evidence of immigration, suggest that this population is demographically self-contained and that both the nearshore and offshore Sakhalin feeding grounds are critically important areas for their summer annual foraging activities. The nearshore habitat is also important for mother-calf pairs, younger individuals, and recently weaned calves. Nearshore feeding could also be energetically less costly compared to foraging in the deeper offshore habitat and provide more protection from predators, such as killer whales.

Sex differences in mechanisms of arterial stiffness.

Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging-related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex-specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex-specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males and females. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex-specific therapies to lessen CVD risk, the leading cause of death in males and females. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Paraffin-embedding lithography and micro-dissected tissue micro-arrays: tools for biological and pharmacological analysis of ex vivo solid tumors.

There is an urgent need and strong clinical and pharmaceutical interest in developing assays that allow for the direct testing of therapeutic agents on primary tissues. Current technologies fail to provide the required sample longevity, throughput, and integration with standard clinically proven assays to make the approach viable. Here we report a microfluidic micro-histological platform that enables ex vivo culture of a large array of prostate and ovarian cancer micro-dissected tissue (MDT) followed by direct on-chip fixation and paraffination, a process we term paraffin-embedding lithography (PEL). The result is a high density MDT-Micro Array (MDTMA) compatible with standard clinical histopathology that can be used to analyse ex vivo tumor response or resistance to therapeutic agents. The cellular morphology and tissue architecture are preserved in MDTs throughout the 15 day culture period. We also demonstrate how this methodology can be used to study molecular pathways involved in cancer by performing in-depth characterization of biological and pharmacological mechanisms such as p65 nuclear translocation via TNF stimuli, and to predict the treatment outcome in the clinic via MDT response to taxane-based therapies.

No Significant Role for Smooth Muscle Cell Mineralocorticoid Receptors in Atherosclerosis in the Apolipoprotein-E Knockout Mouse Model.

Objective: Elevated levels of the hormone aldosterone are associated with increased risk of myocardial infarction and stroke in humans and increased progression and inflammation of atherosclerotic plaques in animal models. Aldosterone acts through the mineralocorticoid receptor (MR) which is expressed in vascular smooth muscle cells (SMCs) where it promotes SMC calcification and chemokine secretion in vitro. The objective of this study is to explore the role of the MR specifically in SMCs in the progression of atherosclerosis and the associated vascular inflammation in vivo in the apolipoprotein E knockout (ApoE-/-) mouse model. Methods and Results: Male ApoE-/- mice were bred with mice in which MR could be deleted specifically from SMCs by tamoxifen injection. The resulting atheroprone SMC-MR-KO mice were compared to their MR-Intact littermates after high fat diet (HFD) feeding for 8 or 16 weeks or normal diet for 12 months. Body weight, tail cuff blood pressure, heart and spleen weight, and serum levels of glucose, cholesterol, and aldosterone were measured for all mice at the end of the treatment period. Serial histologic sections of the aortic root were stained with Oil Red O to assess plaque size, lipid content, and necrotic core area; with PicroSirius Red for quantification of collagen content; by immunofluorescent staining with anti-Mac2/Galectin-3 and anti-smooth muscle α-actin antibodies to assess inflammation and SMC marker expression; and with Von Kossa stain to detect plaque calcification. In the 16-week HFD study, these analyses were also performed in sections from the brachiocephalic artery. Flow cytometry of cell suspensions derived from the aortic arch was also performed to quantify vascular inflammation after 8 and 16 weeks of HFD. Deletion of the MR specifically from SMCs did not significantly change plaque size, lipid content, necrotic core, collagen content, inflammatory staining, actin staining, or calcification, nor were there differences in the extent of vascular inflammation between MR-Intact and SMC-MR-KO mice in the three experiments. Conclusion: SMC-MR does not directly contribute to the formation, progression, or inflammation of atherosclerotic plaques in the ApoE-/- mouse model of atherosclerosis. This indicates that the MR in non-SMCs mediates the pro-atherogenic effects of MR activation.

Fluorescence hyperspectral imaging for live monitoring of multiple spheroids in microfluidic chips.

Tumor spheroids represent a realistic 3D in vitro cancer model because they provide a missing link between monolayer cell culture and live tissues. While microfluidic chips can easily form and assay thousands of spheroids simultaneously, few commercial instruments are available to analyze this massive amount of data. Available techniques to measure spheroid response to external stimuli, such as confocal imaging and flow cytometry, are either not appropriate for 3D cultures, or destructive. We designed a wide-field hyperspectral imaging system to analyze multiple spheroids trapped in a microfluidic chip in a single acquisition. The system and its fluorescence quantification algorithm were assessed using liquid phantoms mimicking spheroid optical properties. Spectral unmixing was tested on three overlapping spectral entities. Hyperspectral images of co-culture spheroids expressing two fluorophores were compared with confocal microscopy and spheroid growth was measured over time. The system can spectrally analyze multiple fluorescent markers simultaneously and allows multiple time-points assays, providing a fast and versatile solution for analyzing lab on a chip devices.

Sex-Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors.

BACKGROUND: The incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors. METHODS AND RESULTS: Male and female endothelial cell-specific MR knockout mice and MR-intact littermates were randomized to high-fat-diet-induced obesity or obesity with hyperlipidemia induced by adeno-associated virus-based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity-induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium-derived hyperpolarization-mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium-derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of H2O2-mediated vasodilation, and increased superoxide production. Endothelial cell-MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium-derived hyperpolarization in females, endothelial cell-MR deletion enhanced nitric oxide and prevented hyperlipidemia-induced oxidative stress. CONCLUSIONS: These data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.

Smooth Muscle Cell-Mineralocorticoid Receptor as a Mediator of Cardiovascular Stiffness With Aging.

Stiffening of the vasculature with aging is a strong predictor of adverse cardiovascular events, independent of all other risk factors including blood pressure, yet no therapies target this process. MRs (mineralocorticoid receptors) in smooth muscle cells (SMCs) have been implicated in the regulation of vascular fibrosis but have not been explored in vascular aging. Comparing SMC-MR-deleted male mice to MR-intact littermates at 3, 12, and 18 months of age, we demonstrated that aging-associated vascular stiffening and fibrosis are mitigated by MR deletion in SMCs. Progression of cardiac stiffness and fibrosis and the decline in exercise capacity with aging were also mitigated by MR deletion in SMC. Vascular gene expression profiling analysis revealed that MR deletion in SMC is associated with recruitment of a distinct antifibrotic vascular gene expression program with aging. Moreover, long-term pharmacological inhibition of MR in aged mice prevented the progression of vascular fibrosis and stiffness and induced a similar antifibrotic vascular gene program. Finally, in a small trial in elderly male humans, short-term MR antagonism produced an antifibrotic signature of circulating biomarkers similar to that observed in the vasculature of SMC-MR-deleted mice. These findings suggest that SMC-MR contributes to vascular stiffening with aging and is a potential therapeutic target to prevent the progression of aging-associated vascular fibrosis and stiffness.

Iron-Catalyzed Reductive Ethylation of Imines with Ethanol.

The borrowing hydrogen strategy has been applied to the ethylation of imines with an air-stable iron complex as precatalyst. This approach opens new perspectives in this area as it enables the synthesis of unsymmetric tertiary amines from readily available substrates and ethanol as a C2 building block. A variety of imines bearing electron-rich aryl or alkyl groups at the nitrogen atom could be efficiently reductively alkylated without the need for molecular hydrogen. The mechanism of this reaction, which shows complete selectivity for ethanol over other alcohols, has been studied experimentally and by means of DFT computations.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature.

Since the mineralocorticoid receptor (MR) was cloned 30 years ago, it has become clear that MR is expressed in extra-renal tissues, including the cardiovascular system, where it is expressed in all cells of the vasculature. Understanding the role of MR in the vasculature has been of particular interest as clinical trials show that MR antagonism improves cardiovascular outcomes out of proportion to changes in blood pressure. The last 30 years of research have demonstrated that MR is a functional hormone-activated transcription factor in vascular smooth muscle cells and endothelial cells. This review summarizes advances in our understanding of the role of vascular MR in regulating blood pressure and vascular function, and its contribution to vascular disease. Specifically, vascular MR contributes directly to blood pressure control and to vascular dysfunction and remodeling in response to hypertension, obesity and vascular injury. The literature is summarized with respect to the role of vascular MR in conditions including: pulmonary hypertension; cerebral vascular remodeling and stroke; vascular inflammation, atherosclerosis and myocardial infarction; acute kidney injury; and vascular pathology in the eye. Considerations regarding the impact of age and sex on the function of vascular MR are also described. Further investigation of the precise molecular mechanisms by which MR contributes to these processes will aid in the identification of novel therapeutic targets to reduce cardiovascular disease (CVD)-related morbidity and mortality.

Short-Term Administration of Serelaxin Produces Predominantly Vascular Benefits in the Angiotensin II/L-NAME Chronic Heart Failure Model.

In patients hospitalized with acute heart failure, temporary serelaxin infusion reduced 6-month mortality through unknown mechanisms. This study therefore explored the cardiovascular effects of temporary serelaxin administration in mice subjected to the angiotensin II (AngII)/L-NG-nitroarginine methyl ester (L-NAME) heart failure model, both during serelaxin infusion and 19 days post-serelaxin infusion. Serelaxin administration did not alter AngII/L-NAME-induced cardiac hypertrophy, geometry, or dysfunction. However, serelaxin-treated mice had reduced perivascular left ventricular fibrosis and preserved left ventricular capillary density at both time points. Furthermore, resistance vessels from serelaxin-treated mice displayed decreased potassium chloride-induced constriction and reduced aortic fibrosis. These findings suggest that serelaxin improves outcomes in patients through vascular-protective effects.