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

Exposure in utero to maternal diabetes leads to glucose intolerance and high blood pressure with no major effects on lipid metabolism

AIM: Recent evidence shows that adult metabolic disease may originate from an adverse fetal environment that can alter organ development and function in postnatal life. This study aimed to analyze the effect of exposure in utero to maternal diabetes on the development of the metabolic syndrome in the offspring. METHODS: Pregnant rats were made diabetic (blood glucose was 20mM) with a single streptozotocin injection on day 0 of gestation. Offspring from diabetic mothers (DMO) and control mothers (CMO) were followed from birth to 12 months of age. In these animals, metabolic parameters, such as glucose tolerance, insulin sensitivity and plasma lipid levels, as well as pancreatic insulin and morphology were studied. RESULTS: Compared with controls, DMO offspring had normal birth weights, but impaired postnatal growth that persisted throughout life. Metabolic tests revealed that DMO offspring also showed impaired glucose tolerance at six months associated with decreased insulin sensitivity and low insulin secretion. In older animals (12 months old), this phenotype persisted, but to a lesser extent. The DMO offspring also presented with high blood pressure and decreased levels of fasting plasma triglycerides, but normal plasma NEFA, and HDL and total cholesterol. CONCLUSION: Altogether, these results show that our model of exposure in utero to maternal diabetes led to normal birth weights, and induced transient glucose intolerance and increased blood pressure with no major effects on lipid metabolism. It also suggests that a hyperglycaemic fetal environment may be able to \u27programme\u27 hypertension and glucose intolerance, but not alter lipid metabolism

Exposure to Maternal Diabetes Is Associated With Early Abnormal Vascular Structure in Offspring

Aim/hypothesis: In utero exposure to maternal diabetes increases the risk of developing hypertension and cardiovascular disorders during adulthood. We have previously shown that this is associated with changes in vascular tone in favor of a vasoconstrictor profile, which is involved in the development of hypertension. This excessive constrictor tone has also a strong impact on vascular structure. Our objective was to study the impact of in utero exposure to maternal diabetes on vascular structure and remodeling induced by chronic changes in hemodynamic parameters. Methods and Results: We used an animal model of rats exposed in utero to maternal hyperglycemia (DMO), which developed hypertension at 6 months of age. At a pre-hypertensive stage (3 months of age), we observed deep structural modifications of the vascular wall without any hemodynamic perturbations. Indeed, in basal conditions, resistance arteries of DMO rats are smaller than those of control mother offspring (CMO) rats; in addition, large arteries like thoracic aorta of DMO rats have an increase of smooth muscle cell attachments to elastic lamellae. In an isolated perfused kidney, we also observed a leftward shift of the flow/pressure relationship, suggesting a rise in renal peripheral vascular resistance in DMO compared to CMO rats. In this context, we studied vascular remodeling in response to reduced blood flow by in vivo mesenteric arteries ligation. In DMO rats, inward remodeling induced by a chronic reduction in blood flow (1 or 3 weeks after ligation) did not occur by contrast to CMO rats in which arterial diameter decreased from 428 ± 17 μm to 331 ± 20 μm (at 125 mmHg, p = 0.001). In these animals, the transglutaminase 2 (TG2) pathway, essential for inward remodeling development in case of flow perturbations, was not activated in low-flow (LF) mesenteric arteries. Finally, in old hypertensive DMO rats (18 months of age), we were not able to detect a pressure-induced remodeling in thoracic aorta. Conclusions: Our results demonstrate for the first time that in utero exposure to maternal diabetes induces deep changes in the vascular structure. Indeed, the early narrowing of the microvasculature and the structural modifications of conductance arteries could be a pre-emptive adaptation to fetal programming of hypertension

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

Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes

Diabetes Mellitus is associated with severe cardiovascular disorders involving the renin-angiotensin system, mainly through activation of the angiotensin II type 1 receptor (AT1R). Although the type 2 receptor (AT2R) opposes the effects of AT1R, with vasodilator and anti-trophic properties, its role in diabetes is debatable. Thus we investigated AT2R-mediated dilatation in a model of type 1 diabetes induced by streptozotocin in 5-month-old male mice lacking AT2R (AT2R). Glucose tolerance was reduced and markers of inflammation and oxidative stress (cyclooxygenase-2, gp91phox p22phox and p67phox) were increased in AT2R mice compared to wild-type (WT) animals. Streptozotocin-induced hyperglycaemia was higher in AT2R than in WT mice. Arterial gp91phox and MnSOD expression levels in addition to blood 8-isoprostane and creatinine were further increased in diabetic AT2R mice compared to diabetic WT mice. AT2R-dependent dilatation in both isolated mesenteric resistance arteries and perfused kidneys was greater in diabetic mice than in non-diabetic animals. Thus, in type 1 diabetes, AT2R may reduce glycaemia and display anti-oxidant and/or anti-inflammatory properties in association with greater vasodilatation in mesenteric arteries and in the renal vasculature, a major target of diabetes. Therefore AT2R might represent a new therapeutic target in diabetes

Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed In Utero to Maternal Hyperglycaemia

Epidemiologic studies have demonstrated that cardiovascular risk is not only determined by conventional risk factors in adulthood, but also by early life events which may reprogram vascular function. To evaluate the effect of maternal diabetes on fetal programming of vascular tone in offspring and its evolution during adulthood, we investigated vascular reactivity of third order mesenteric arteries from diabetic mother offspring (DMO) and control mother offspring (CMO) aged 3 and 18 months. In arteries isolated from DMO the relaxation induced by prostacyclin analogues was reduced in both 3- and 18-month old animals although endothelium (acetylcholine)-mediated relaxation was reduced in 18-month old DMO only. Endothelium-independent (sodium nitroprusside) relaxation was not affected. Pressure-induced myogenic tone, which controls local blood flow, was reduced in 18-month old CMO compared to 3-month old CMO. Interestingly, myogenic tone was maintained at a high level in 18-month old DMO even though agonist-induced vasoconstriction was not altered. These perturbations, in 18-months old DMO rats, were associated with an increased pMLC/MLC, pPKA/PKA ratio and an activated RhoA protein. Thus, we highlighted perturbations in the reactivity of resistance mesenteric arteries in DMO, at as early as 3 months of age, followed by the maintenance of high myogenic tone in older rats. These modifications are in favour of excessive vasoconstrictor tone. These results evidenced a fetal programming of vascular functions of resistance arteries in adult rats exposed in utero to maternal diabetes, which could explain a re-setting of vascular functions and, at least in part, the occurrence of hypertension later in life

Selective involvement of serum response factor in pressure-induced myogenic tone in resistance arteries

OBJECTIVE: In resistance arteries, diameter adjustment in response to pressure changes depends on the vascular cytoskeleton integrity. Serum response factor (SRF) is a dispensable transcription factor for cellular growth, but its role remains unknown in resistance arteries. We hypothesized that SRF is required for appropriate microvascular contraction. METHODS AND RESULTS: We used mice in which SRF was specifically deleted in smooth muscle or endothelial cells, and their control. Myogenic tone and pharmacological contraction was determined in resistance arteries. mRNA and protein expression were assessed by quantitative real-time PCR (qRT-PCR) and Western blot. Actin polymerization was determined by confocal microscopy. Stress-activated channel activity was measured by patch clamp. Myogenic tone developing in response to pressure was dramatically decreased by SRF deletion (5.9+/-2.3%) compared with control (16.3+/-3.2%). This defect was accompanied by decreases in actin polymerization, filamin A, myosin light chain kinase and myosin light chain expression level, and stress-activated channel activity and sensitivity in response to pressure. Contractions induced by phenylephrine or U46619 were not modified, despite a higher sensitivity to p38 blockade; this highlights a compensatory pathway, allowing normal receptor-dependent contraction. CONCLUSIONS: This study shows for the first time that SRF has a major part to play in the control of local blood flow via its central role in pressure-induced myogenic tone in resistance arteries

Exposure to Maternal Diabetes Induces Salt-Sensitive Hypertension and Impairs Renal Function in Adult Rat Offspring

OBJECTIVE—Epidemiological and experimental studies have led to the hypothesis of fetal origin of adult diseases, suggesting that some adult diseases might be determined before birth by altered fetal development. We have previously demonstrated in the rat that in utero exposure to maternal diabetes impairs renal development leading to a reduction in nephron number. Little is known on the long-term consequences of in utero exposure to maternal diabetes. The aim of the study was to assess, in the rat, long-term effects of in utero exposure to maternal diabetes on blood pressure and renal function in adulthood

HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS

Pénétration de l'hémoglobine issue des substituts érythrocytaires au sein des cellules endothéliales aortiques in vivo chez le cobaye

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