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Elimination of vitamin D receptor in vascular endothelial cells alters vascular function.

ABSTRACT: Vitamin D deficiency has been associated with cardiovascular dysfunction. We evaluated the role of the vitamin D receptor (VDR) in vascular endothelial function, a marker of cardiovascular health, at baseline and in the presence of angiotensin II, using an endothelial-specific knockout of the murine VDR gene. In the absence of endothelial VDR, acetylcholine-induced aortic relaxation was significantly impaired (maximal relaxation, endothelial-specific VDR knockout=58% versus control=73%; P<0.05). This was accompanied by a reduction in endothelial NO synthase expression and phospho-vasodilator-stimulated phosphoprotein levels in aortae from the endothelial-specific VDR knockout versus control mice. Although blood pressure levels at baseline were comparable at 12 and 24 weeks of age, the endothelial VDR knockout mice demonstrated increased sensitivity to the hypertensive effects of angiotensin II compared with control mice (after 1-week infusion: knockout=155±15 mm Hg versus control=133±7 mm Hg; P<0.01; after 2-week infusion: knockout=164±9 mm Hg versus control=152±13 mm Hg; P<0.05). By the end of 2 weeks, angiotensin II infusion-induced, hypertrophy-sensitive myocardial gene expression was higher in endothelial-specific VDR knockout mice (fold change compared with saline-infused control mice, type-A natriuretic peptide: knockout mice=3.12 versus control=1.7; P<0.05; type-B natriuretic peptide: knockout mice=4.72 versus control=2.68; P<0.05). These results suggest that endothelial VDR plays an important role in endothelial cell function and blood pressure control and imply a potential role for VDR agonists in the management of cardiovascular disease associated with endothelial dysfunction.

SUBMITTER: Ni W

PROVIDER: S-EPMC4430199 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Project description:BackgroundReceptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endothelial growth factor receptors (VEGFRs) and G protein-coupled receptors, which classically activate distinct intracellular signaling pathways and responses. The mechanisms that regulate these signaling pathways have not been fully elucidated and it is unclear what nodes for cross talk exist between these diverse signaling pathways. For example, multifunctional β-arrestin (ARRB) adapter proteins are best known as regulators of G protein-coupled receptor signaling, but their role at other receptors and their physiological importance in the setting of vascular disease are unclear.MethodsWe used a combination of human samples from PAH, human microvascular endothelial cells from lung, and Arrb knockout mice to determine the role of ARRB1 in endothelial VEGFR3 signaling. In addition, a number of biochemical analyses were performed to determine the interaction between ARRB1 and VEGFR3, signaling mediators downstream of VEGFR3, and the internalization of VEGFR3.ResultsExpression of ARRB1 and VEGFR3 was reduced in human PAH, and the deletion of Arrb1 in mice exposed to hypoxia led to worse PAH with a loss of VEGFR3 signaling. Knockdown of ARRB1 inhibited VEGF-C-induced endothelial cell proliferation, migration, and tube formation, along with reduced VEGFR3, Akt, and endothelial nitric oxide synthase phosphorylation. This regulation was mediated by direct ARRB1 binding to the VEGFR3 kinase domain and resulted in decreased VEGFR3 internalization.ConclusionsOur results demonstrate a novel role for ARRB1 in VEGFR regulation and suggest a mechanism for cross talk between G protein-coupled receptors and VEGFRs in PAH. These findings also suggest that strategies to promote ARRB1-mediated VEGFR3 signaling could be useful in the treatment of pulmonary hypertension and other vascular disease.

Project description:Vascular endothelial cells are crucial mediators of inflammation during infectious diseases, due to their ability to produce lipid-based inflammatory mediators and facilitate leukocyte migration and translocation to infected tissues. Mastitis is the costliest infectious disease in North America, with over two billion dollars in annual costs due to loss of milk production, medical treatment, and potential loss of the animal. Infections caused by coliform bacteria are particularly deleterious, causing a negative impact on cow well-being and a high mortality rate. Dysfunction and breakdown of the endothelial barrier is a key part of the pathology of coliform mastitis. The endocannabinoid system (ECS), shown to modulate inflammatory responses of vascular endothelial cells in humans and rodents, may be a novel target for inflammatory modulation in dairy cows. The endocannabinoid (EC) arachidonoylethanolamide (AEA) is a potent anti- or pro-inflammatory mediator in endothelial cells, depending on location, timing, and concentration. We hypothesized that elevated AEA during LPS challenge will impair endothelial barrier integrity via increased production of reactive oxygen species (ROS) and activation of apoptotic pathways. Challenge of bovine aortic endothelial cells (BAEC) with 25 ng/mL lipopolysaccharide (LPS) for 8 h induced AEA synthesis, increased expression of cannabinoid receptor 1 and 2 (CB1/2) and the AEA synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), while decreasing gene expression of the AEA degradation enzyme fatty acid amide hydrolase (FAAH). Trans endothelial resistance (TER), measured through electrical resistance across the monolayer, increased 2 h after 0.5 µM AEA treatment and decreased with 5 µM AEA, compared to LPS alone. Addition of AEA to BAEC challenged with LPS induced mitochondrial dysfunction via increased ROS production, cytochrome-C release, and activation of caspase 3/7. Antagonism of CB1 by 1 µM AM251 ameliorated AEA induced ROS production and cytochrome-C release. Addition of AM251 also eliminated 2 h TER increase and improved TER following 5 µM AEA. Doses of 0.5, 1, and 5 µM AEA delayed endothelial barrier recovery, which was eliminated by the addition of AM251. Mitochondrial dysfunction and activation of apoptotic pathways in response to AEA treatment during LPS challenge of BAEC may act to delay inflammatory resolution and contribute to endothelial dysfunction.

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Elimination of vitamin D receptor in vascular endothelial cells alters vascular function.

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