Biology subjects

Vestweber, D.

Publications and source records attributed to Vestweber, D..

3 recordsLinked to original sources

bioRxiv2020

eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin

Hypoxia and the production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Therapeutics targeting VEGFA suppress leakiness and edema but aggravate hypoxia; therefore, new therapeutics are needed. We examined the role of endothelial nitric oxide synthase (eNOS) in pathological neovascularization and vessel permeability during oxygen-induced retinopathy. NO formation was suppressed chemically using L-NMMA, or genetically, in eNOS serine to alanine (S1176A) mutant mice, resulting in reduced retinal neoangiogenesis. Both strategies resulted in reduced vascular leakage by stabilizing endothelial adherens junctions through suppressed phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Intervention treatment by a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage. We conclude that eNOS induces destabilization of adherens junctions and vascular hyperpermeability by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway and that this pathway can be selectively inhibited by blocking NO formation.

cell biology↗

bioRxiv2020

A molecular map of lymph node blood vascular endothelium at single cell resolution

Blood vascular endothelial cells (BECs) control the immune response by regulating immune cell recruitment, metabolite exchange and blood flow in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain poorly understood. Here we profile transcriptomes of BEC from mouse peripheral lymph nodes and map key phenotypes to the vasculature. Our analysis identifies multiple novel subsets including a venous population whose gene signature predicts an unexpectedly selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by 2 photon videomicroscopy. We define five phenotypes of capillary lining BEC including a capillary resident regenerative population (CRP) that displays stem cell and migratory gene signatures and contributes to homeostatic BEC turnover and to vascular neogenesis after immunization. Trajectory analyses reveal retention of developmental programs along a progression of cellular phenotypes from CRP to mature venous and arterial BEC subsets. Overall, our single cell atlas provides a molecular blueprint of the lymph node blood vasculature and defines subset specialization for immune cell recruitment and vascular homeostasis.

immunology↗

bioRxiv2018

Hematopoietic Stem And Progenitor Cells Use Podosomes To Transcellularly Home To The Bone Marrow.

Bone marrow (BM) endothelium plays an important role in homing of hematopoietic stem and progenitor cells (HSPCs) upon transplantation, but surprisingly little is known on how endothelial cells regulate local permeability and HSPC transmigration. We show that temporal loss of VE-cadherin function promotes vascular permeability in BM, even upon low dose irradiation and strongly enhanced homing of transplanted HSPCs to BM of irradiated mice. Intriguingly, stabilizing junctional VE-cadherin in vivo reduced BM permeability, but did not prevent HSPC migration into the BM, suggesting that HSPCs enter the bone marrow by transcellularly crossing the endothelium. Indeed, HSPCs induce podosomes to cross human BM endothelial monolayers in a transcellular manner. By contrast, HSPC rather use the paracellular route when VE-cadherin function is inhibited. Taken together, VE-cadherin is crucial for BM vascular homeostasis and HSPC homing, and may therefore serve as a potential therapeutic target to improve HSPC homing strategies.

cell biology↗