Neuropilin-1 interacts with VE-cadherin and TGFBR2 to stabilize adherens junctions and prevent activation of endothelium under flow.

Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression profile and phenotype. Here, we investigated the role of the transmembrane protein neuropilin-1 (NRP1) in ECs exposed to flow using cultured ECs, mice with an endothelium-specific knockout of NRP1, and a mouse model of atherosclerosis. We demonstrated that NRP1 was a constituent of adherens junctions that interacted with VE-cadherin and promoted its association with p120 catenin, stabilizing adherens junctions and inducing cytoskeletal remodeling in alignment with the direction of flow. We also showed that NRP1 interacted with transforming growth factor-ß (TGF-ß) receptor II (TGFBR2) and reduced the plasma membrane localization of TGFBR2 and TGF-ß signaling. NRP1 knockdown increased the abundance of proinflammatory cytokines and adhesion molecules, resulting in increased leukocyte rolling and atherosclerotic plaque size. These findings describe a role for NRP1 in promoting endothelial function and reveal a mechanism by which NRP1 reduction in ECs may contribute to vascular disease by modulating adherens junction signaling and promoting TGF-ß signaling and inflammation.

Empagliflozin prevents angiotensin II-induced hypertension related micro and macrovascular endothelial cell activation and diastolic dysfunction in rats despite persistent hypertension: Role of endothelial SGLT1 and 2.

SGLT2 inhibitors (SGLT2i) showed pronounced beneficial effects in patients with heart failure but the underlying mechanisms remain unclear. We evaluated the effect of empagliflozin, selective SGLT2i, on hypertension-induced cardiac and vascular dysfunction. Male Wistar rats received diet with or without empagliflozin (30 mg/kg/day). After 1 week, a hypertensive dose of Ang II (0.4 mg/kg/day) was administered using osmotic mini-pumps for 4 weeks. Systolic blood pressure was determined by sphygmomanometry, the cardiac function by echocardiography and ex vivo (coronary microvascular endothelial cell activation, LV remodeling and fibrosis responses), and the systemic micro and macrovascular endothelial cell activation ex vivo. Empagliflozin treatment did not affect the Ang II-induced hypertensive response. Ang II treatment increased LV mass and induced LV diastolic dysfunction, fibrosis, collagen I and ANP expression, and infiltration of macrophages. In the vasculature, it caused eNOS upregulation in the aorta and down-regulation in mesenteric microvessels associated with increased oxidative stress, ACE, AT1R, VCAM-1, MCP-1, MMP-2, and MMP-9 and collagen I expression, increased endothelial SGLT1 staining in the aorta, mesenteric and coronary microvessels, increased SGLT1 and 2 protein levels in the aorta. All Ang II-induced cardiac and vascular responses were reduced by the empagliflozin treatment. Thus, the SGLT2i effectively attenuated the deleterious impact of Ang II-induced hypertension on target organs including cardiac diastolic dysfunction and remodeling, and endothelial cell activation and pro-atherosclerotic, pro-fibrotic and pro-remodeling responses in macro and microvessels despite persistent hypertension.

Septic shock as a trigger of arterial stress-induced premature senescence: A new pathway involved in the post sepsis long-term cardiovascular complications.

BACKGROUND: Major adverse cardiovascular events among sepsis survivors is an emerging health issue. Because endothelial senescence leads to vascular dysfunction and atherothrombosis, sepsis could be associated to vascular stress-induced premature senescence and thus with long-term cardiovascular events. MATERIALS & METHODS: Adult Wistar male rats were submitted to cecal ligation and puncture, or a SHAM operation. Markers of inflammation, oxidative stress and endothelial senescence were assessed at 3, 7 and 90 days (D), and vascular reactivity was assessed in conductance and resistance vessels at D90. Expression of proteins involved in senescence and inflammation was assessed by Western blot analysis and confocal microscopy, oxidative stress by dihydroethidium probing. RESULTS: Pro-inflammatory endothelial ICAM-1 and VCAM-1 were up-regulated by three-fold in CLP vs. SHAM at D7 and remained elevated at D90. Oxidative stress followed a similar pattern but was detected in the whole vascular wall. Sepsis accelerated premature senescence in aorta vascular tissue as shown by the significant up-regulation of p53 and down-stream p21 and p16 senescent markers at D7, values peaking at D90 whereas the absence of significant variation in activated caspase-3 confirmed p53 as a prime inducer of senescence. In addition, p53 was mainly expressed in the endothelium. Sepsis-induced long-term vascular dysfunction was confirmed in aorta and main mesenteric artery, with a major alteration of the endothelial-dependent nitric oxide pathway. CONCLUSIONS: Septic shock-induced long-term vascular dysfunction is associated with endothelial and vascular senescence. Our model could prove useful for investigating senotherapies aiming at reducing long-term cardiovascular consequences of septic shock.