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The BReast CAncer type 2 susceptibility protein (BRCA2) responds to DNA damage by participating in homology-directed repair. BRCA2 deficiency culminates in defective DNA damage repair (DDR) that when prolonged leads to the accumulation of DNA damage causing cancer or apoptosis. Oxidative stress promotes DNA damage and apoptosis and is a common mechanism through which cardiovascular risk factors lead to endothelial dysfunction and atherosclerosis. Herein, we show that endothelial BRCA2 plays a protective role against atherosclerosis under hypercholesterolemic stress. We successfully generated and characterized endothelial cell (EC)-specific BRCA2 knockout (BRCA2endo) mice. To study the effect of EC-specific BRCA2-loss in atherosclerosis, we generated and characterized BRCA2endo mice on apolipoprotein E null background (ApoE-/-), fed them with high-fat diet (HFD) and evaluated atherosclerosis. Baseline phenotyping of BRCA2endo mice did not show any adverse effects in terms of DNA damage and apoptosis as well as cardiac and metabolic function. However, using HFD-fed apolipoprotein E knockout (ApoE-/-) background, we demonstrated that EC-specific loss of BRCA2 resulted in aortic plaque deposition and splenomegaly. Comparison of RNA sequencing data from aortas of EC-specific BRCA2-deficient ApoE-/- and BRCA2-intact ApoE-/- mice revealed a total of 530 significantly differentially expressed genes with Protein Folding Response and Lipid Metabolism as the most affected pathways. This study provides foundational knowledge regarding BRCA2 status and function in the cardiovascular system, and highlights the potential of BRCA2 as a novel therapeutic target in prevention and treatment of atherosclerosis. Our data indicate that BRCA2 mutation carriers may be at a previously unrecognized risk of atherosclerosis in addition to breast and ovarian cancer.

With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGIWhile research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17 weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25 μm (post-capillary) and ∼75 μm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α

A major challenge facing public health is the increased incidence and prevalence of the metabolic syndrome, a clinical condition characterized by excess adiposity, impaired glycaemic control, dyslipidaemia and moderate hypertension. The greatest concern for this syndrome is the profound increase in risk for development of peripheral vascular disease (PVD) in afflicted persons. However, ongoing studies suggest that reductions in bulk blood flow to skeletal muscle may not be the primary contributor to the premature muscle fatigue that is a hallmark of PVD. Compelling evidence has been provided suggesting that an increasingly spatially heterogeneous and temporally stable distribution of blood flow at successive arteriolar bifurcations in metabolic syndrome creates an environment where a large number of the pre‐capillary arterioles have low perfusion, low haematocrit, and are increasingly confined to this state, with limited ability to adapt perfusion in response to a challenged environment. Single pharmacological interventions are unable to significantly restore function owing to a divergence in their spatial effectiveness, although combined therapeutic approaches to correct adrenergic dysfunction, elevated oxidant stress and increased thromboxane A2 improve perfusion‐based outcomes. Integrated, multi‐target therapeutic interventions designed to restore healthy network function and flexibility may provide for superior outcomes in subjects with metabolic syndrome‐associated PVD.