Epidermal growth factor receptor mediates the vascular dysfunction but not the remodeling induced by aldosterone/salt

Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine- and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress

The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure

Pathophysiological aldosterone (aldo)/mineralocorticoid receptor (MR) signaling has significant effects on the cardiovascular system, resulting in hypertension and cardiovascular remodeling; however, the specific contribution of the vascular MR to blood pressure regulation remains to be established. To address this question, we generated a mouse model with conditional overexpression of the MR in endothelial cells (MR-EC). In basal conditions, MR-EC mice developed moderate hypertension that could be reversed by canrenoate, a pharmacological MR antagonist. MR-EC mice presented increased contractile response of resistance arteries to vasoconstrictors (phenylephrine, thromboxane A(2) analog, angiotensin II, and endothelin 1) in the absence of vascular morphological alterations. The acute blood pressure response to angiotensin II or endothelin 1 infusion was increased in MR-EC mice compared with that in littermate controls. These observations demonstrate that enhanced MR activation in the endothelium generates an increase in blood pressure, independent of stimulation of renal tubular Na(+) transport by aldo/MR or direct activation of smooth muscle MR and establish one mechanism by which endothelial MR activation per se may contribute to impaired vascular reactivity

Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction

Experimental studies showed that 17{beta}-estradiol (E2) and activated Estrogen Receptors (ER) protect the heart from ischemic injury. However, the underlying molecular mechanisms are not well understood. To investigate the role of ER{alpha} in cardiomyocytes in the setting of myocardial ischemia, we generated transgenic mice with cardiomyocyte-specific overexpression of ER-{alpha} (ER{alpha}-OE) and subjected them to Myocardial Infarction (MI). At the basal level, female and male ER{alpha}-OE mice showed increased Left Ventricular (LV) mass, LV volume and cardiomyocyte length. Two weeks after MI, LV volume was significantly increased and LV wall thickness decreased in female and male WT-mice and male ER{alpha}-OE, but not in female ER{alpha}-OE mice. ER{alpha}-OE enhanced expression of angiogenesis and lymphangiogenesis markers (Vegf, Lyve-1), and neovascularization in the peri-infarct area in both sexes. However, attenuated level of fibrosis and higher phosphorylation of JNK signaling pathway could be detected only in female ER{alpha}-OE after MI. In conclusion, our study indicates that ER{alpha} protects female mouse cardiomyocytes from the sequelae of ischemia through induction of neovascularization in a paracrine fashion and impaired fibrosis, which together may contribute to the attenuation of cardiac remodelling

Smooth muscle cell-specific knockout of neuropilin-1 impairs postnatal lung development and pathological vascular smooth muscle cell accumulation

Neuropilin 1 (NRP1) is important for neuronal and cardiovascular development due to its role in conveying class 3 semaphorin and vascular endothelial growth factor signaling, respectively. NRP1 is expressed in smooth muscle cells (SMCs) and mediates their migration and proliferation in cell culture and is implicated in pathological SMC remodeling in vivo. To address the importance of Nrp1 for SMC function during development, we generated conditional inducible Nrp1 SMC-specific knockout mice. Induction of early postnatal SMC-specific Nrp1 knockout led to pulmonary hemorrhage associated with defects in alveogenesis and revealed a specific requirement for Nrp1 in myofibroblast recruitment to the alveolar septae and PDGF-AA-induced migration in vitro. Furthermore, SMC-specific Nrp1 knockout inhibited PDGF-BB-stimulated SMC outgrowth ex vivo in aortic ring assays and reduced pathological arterial neointima formation in vivo. In contrast, we observed little significant effect of SMC-specific Nrp1 knockout on neonatal retinal vascularization. Our results point to a requirement of Nrp1 in vascular smooth muscle and myofibroblast function in vivo, which may have relevance for postnatal lung development and for pathologies characterized by excessive SMC and/or myofibroblast proliferation

Endothelial mineralocorticoid receptor activation enhances endothelial protein C receptor and decreases vascular thrombosis in mice

Previous studies have shown that aldosterone, which activates the mineralocorticoid receptor (MR), promotes thrombosis in animal models. Our objective was to determine whether MR activation/expression in the vascular endothelium could modify thrombotic risk in vivo and to examine thrombin generation at the surface of aortic endothelial cells (HAECs). MR was conditionally overexpressed in vivo in vascular endothelial cells in mice (MR-EC mice) or stimulated with aldosterone in HAECs. Thrombosis after ferric chloride injury was delayed in MR-EC mice compared with controls as well as in wild-type FVB/NRj mice treated with aldosterone (60 mug/kg/d for 21 d). Thrombin generation in platelet-poor plasma did not differ between MR-EC mice and controls. In MR-EC mice, aortic endothelial cell protein C receptor (EPCR) expression was increased. Aldosterone (10(-8) M) attenuated thrombin generation at the surface of cultured HAECs, and this effect was associated with up-regulation of expression of EPCR, which promotes formation of activated protein C. Aldosterone increases EPCR expression via a transcriptional mechanism involving interaction of MR with the specificity protein 1 site. These findings demonstrate that MR activation acts on endothelial cells to protect against thrombosis in physiological conditions and that MR-mediated EPCR overexpression drives this antithrombotic property through enhancing protein C activation

Lipocalin 2 as a potential systemic biomarker for central serous chorioretinopathy

No systemic biomarker of Central Serous Chorioretinopathy (CSCR) has been identified. Lipocalin 2 (LCN2 or NGAL), alone or complexed with MMP-9 (NGAL/MMP-9), is increased in several retinal disorders. Serum levels of LCN2 and NGAL/MMP-9 were measured in CSCR patients (n = 147) with chronic (n = 76) or acute/recurrent disease (n = 71) and in age- and sex-matched

Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration.

Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin. Intravitreal injections of spironolactone-loaded microspheres and systemic delivery lead to similar reductions in CNV. Together, our work suggests MR inhibition as a novel therapeutic option for wet AMD patients unresponsive to anti-VEGF drugs

Development of a Chromosomally Integrated Metabolite-Inducible Leu3p-α-IPM “Off-On” Gene Switch

Background: Present technology uses mostly chimeric proteins as regulators and hormones or antibiotics as signals to induce spatial and temporal gene expression. Methodology/Principal Findings: Here, we show that a chromosomally integrated yeast ‘Leu3p-a-IRM ’ system constitutes a ligand-inducible regulatory ‘‘off-on’ ’ genetic switch with an extensively dynamic action area. We find that Leu3p acts as an active transcriptional repressor in the absence and as an activator in the presence of a-isopropylmalate (a-IRM) in primary fibroblasts isolated from double transgenic mouse embryos bearing ubiquitously expressing Leu3p and a Leu3p regulated GFP reporter. In the absence of the branched amino acid biosynthetic pathway in animals, metabolically stable a-IPM presents an EC 50 equal to 0.8837 mM and fast ‘‘OFF-ON’ ’ kinetics (t 50ON = 43 min, t 50OFF = 2.18 h), it enters the cells via passive diffusion, while it is non-toxic to mammalian cells and to fertilized mouse eggs cultured ex vivo. Conclusions/Significance: Our results demonstrate that the ‘Leu3p-a-IRM ’ constitutes a simpler and safer system for inducible gene expression in biomedical applications