Vav3-induced cytoskeletal dynamics contribute to heterotypic properties of endothelial barriers

Abstract

Through multiple cell-cell and cell-matrix interactions, epithelial and endothelial sheets form tight barriers. Modulators of the cytoskeleton contribute to barrier stability and act as rheostats of vascular permeability. In this study, we sought to identify cytoskeletal regulators that underlie barrier diversity across vessels. To achieve this, we correlated functional and structural barrier features to gene expression of endothelial cells (ECs) derived from different vascular beds. Within a subset of identified candidates, we found that the guanosine nucleotide exchange factor Vav3 was exclusively expressed by microvascular ECs and was closely associated with a high-resistance barrier phenotype. Ectopic expression of Vav3 in large artery and brain ECs significantly enhanced barrier resistance and cortical rearrangement of the actin cytoskeleton. Mechanistically, we found that the barrier effect of Vav3 is dependent on its Dbl homology domain and downstream activation of Rap1. Importantly, inactivation of Vav3 in vivo resulted in increased vascular leakage, highlighting its function as a key regulator of barrier stability.

Myosin IIA–mediated forces regulate multicellular integrity during vascular sprouting

“…For example, the entirety of the in vitro studies presented in this work were completed using HUVECs as the model cell type. Though HUVECs have been utilized extensively in a broad range of in vitro angiogenesis studies, recent work highlighting differential functions of ECs from specific organs or levels of the vascular hierarchy (Rafii et al, 2016; Hilfenhaus et al, 2018) opens the possibility that the role of NMII in sprout morphogenesis could vary across EC subtypes. Additionally, the in vitro angiogenesis studies carried out in this work have been done utilizing acellular collagen matrices in the absence of supportive cell types such as pericytes and other tissue-specific mural cells; both matrix composition and these ancillary cells have been demonstrated to impact vascular network formation, sprouting, and barrier function (Ribatti et al, 2011; Rao et al, 2012; Kim et al, 2015; Alimperti et al, 2017).…”

Rap1 Small GTPase Regulates Vascular Endothelial-Cadherin-Mediated Endothelial Cell–Cell Junctions and Vascular Permeability

“…The transcription factor lymphoblastic leukemia-derived sequence 1 (Lyl1), a member of the basic helix-loop-helix family, is known to specifically be expressed in hematopoietic and endothelial cells during development as well as in adulthood. 65) Lyl1-deficient mice showed increased pulmonary vascular permeability as compared to wild type mice. 65) It is noteworthy that endothelial cells derived from Lyl1-deficient mice exhibited reduced expressions of C3G and Dock4 (an atypical GEF for Rap1) mRNAs and increased Rho activity, raising the possibility that downregulated Rap1 activity might account for the elevation in pulmonary vascular permeability observed in the Lyl1-deficient mice.…”

The Vav GEF Family: An Evolutionary and Functional Perspective

“…Further functions of Vav3 inside the nervous system include the blockage of the differentiation of oligodendrocyte precursors and the promotion of myelination processes during both development and injury recovery [127]. Outside the central nervous system, Vav3 has been linked to the regulation of the differentiation of progenitor cells during the development of the mouse retina, the permeability of endothelial cells, the maturation of osteoclasts, and the regulation of antifungal innate immunity [95,128,129,130].…”