To establish the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell functions, we investigated the effect of phosphorylation of a VE-cadherin site sought to be involved in p120-catenin binding on vascular permeability and endothelial cell migration. To this end, we introduced either wild-type VE-cadherin or Y658 phosphomimetic (Y658E) or dephosphomimetic (Y658F) VE-cadherin mutant constructs into an endothelial cell line (rat fat pad endothelial cells) lacking endogenous VE-cadherin. Remarkably, neither wild-type- nor Y658E VE-cadherin was retained at cell-cell contacts because of p120-catenin preferential binding to N-cadherin, resulting in the targeting of N-cadherin to cell-cell junctions and the exclusion of VE-cadherin. However, Y658F VE-cadherin was able to bind p120-catenin and to localize at adherence junctions displacing N-cadherin. This resulted in an enhanced barrier function and a complete abrogation of Rac1 activation and lamellipodia formation, thereby inhibiting cell migration. These findings demonstrate that VE-cadherin, through the regulation of Y658 phosphorylation, competes for junctional localization with N-cadherin and controls vascular permeability and endothelial cell migration.

The fibroblast growth factor (FGF) system plays a critical role in the maintenance of vascular integrity via enhancing the stability of VE-cadherin at adherens junctions. However, the precise molecular mechanism is not well understood. In the present study, we aimed to investigate the detailed mechanism of FGF regulation of VE-cadherin function that leads to endothelial junction stabilization. In vitro studies demonstrated that the loss of FGF signaling disrupts the VE-cadherin-catenin complex at adherens junctions by increasing tyrosine phosphorylation levels of VE-cadherin. Among protein tyrosine phosphatases (PTPs) known to be involved in the maintenance of the VE-cadherin complex, suppression of FGF signaling reduces SHP2 expression levels and SHP2/VE-cadherin interaction due to accelerated SHP2 protein degradation. Increased endothelial permeability caused by FGF signaling inhibition was rescued by SHP2 overexpression, indicating the critical role of SHP2 in the maintenance of endothelial junction integrity. These results identify FGF-dependent maintenance of SHP2 as an important new mechanism controlling the extent of VE-cadherin tyrosine phosphorylation, thereby regulating its presence in adherens junctions and endothelial permeability.

As our understanding of molecular mechanisms leading to vascular formation increases, vessel maintenance including stabilization of new vessels and prevention of vessel regression began to be considered as an active process that requires specific cellular signaling. While signaling pathways such as VEGF, FGF, and angiopoietin-Tie2 are important for endothelial cell survival and junction stabilization, PDGF and TGF-βsignaling modify mural cell (vascular smooth muscle cells and pericytes) functions, thus they fortify vessel integrity. Breakdown of these signaling systems results in pathological hyperpermeability and/or genetic vascular abnormalities such as vascular malformations, ultimately progressing to hemorrhage and edema. Hence, blood vessel maintenance is fundamental to controlling vascular homeostasis and tissue functions. This paper discusses signaling pathways essential for vascular maintenance and clinical conditions caused by deterioration of vessel integrity.

In embryonic hearts explanted on collagen gels, epicardial cells delaminate and form vascular tubes, thus providing a model for coronary tubulogenesis. Using this model, we show that fibroblast growth factors (FGFs) 1, 2, 4, 8, 9, and 18 contribute to tubulogenesis and that the availability of multiple FGFs provides the optimal tubulogenic response. Moreover, the FGF effects are vascular endothelial growth factor (VEGF) ‐dependent, while VEGF‐induced tubulogenesis requires FGF signaling. The number of endothelial cells (ECs) is increased by all of the FGFs, while EC migration is significantly enhanced only by FGF‐2 and FGF‐18. Finally, addition of embryonic mesenchymal stem cells (EMSC) to the explants markedly enhances EC numbers and a 23‐fold increase in stromal derived factor‐1α (SDF‐1α), which is FGF dependent. Both explants and EMSCs produce SDF‐1α. In conclusion, coronary tubulogenesis of embryonic epicardium: (1) is responsive to many FGF family members, (2) requires both FGF and VEGFA signaling, and (3) is responsive to EMSCs. Developmental Dynamics 239:3182–3191, 2010.

Background: Gastric wall edema has not been reported as a complication of acute pancreatitis in dogs. Objective: To describe the ultrasonographic features of gastric wall thickening in dogs with acute pancreatitis. Animals: Fourteen dogs with ultrasonographic evidence and clinical diagnosis of acute pancreatitis, with ultrasonographic evidence of increased gastric wall thickness (>5 mm). Methods: A retrospective search in the medical records from 2014 to 2016 was performed to identify dogs that had ultrasonographic evidence of acute pancreatitis, that had increased thickness of the gastric wall and that were diagnosed with acute pancreatitis clinically. The gastric wall changes such as thickness, layering appearance, echogenicity, distribution of lesions, and perigastric changes were recorded. Serial ultrasonographic examination and histopathological findings were recorded if available. Results: Mean gastric wall thickness was 9.9 ± 4.0 mm (SD). A complete loss of wall layering was observed in 2 dogs. Thickening of the submucosal layer was observed in 12 dogs, and 5 of them had concurrent muscularis layer thickening. The echogenicity of thickened submucosal layer was intermediate hyperechoic. Lacy appearances were present within the thickened submucosal layer in 7 dogs and in the muscularis layer of 1 dog. Thickening was focal in 12 dogs and adjacent to the diseased pancreas. Subsequent resolution of gastric wall thickening was observed in 3 dogs (range 3-28 days) via follow-up ultrasound. One dog underwent necropsy, and gastric wall edema was confirmed histopathologically. Conclusions and Clinical Importance: Findings indicated that gastric wall thickening presumably because of edema could be a complication of acute pancreatitis.

Oral immunization is a safe and easily applicable route to induce mucosal immunity to HIV infection. We examined the ability of oral attenuated Salmonella typhimurium (ST) vaccine expressing Gag for the efficiency of generating Gag-specific mucosal IgA and CD8+ T cell responses in intestinal lymphoid tissues. By optimizing the codon of HIV-1 gag to the preferred codon bias of Salmonella, the expression of Gag in Salmonella was dramatically improved. The oral ST-Gag vaccine by itself was not so powerful and induces little Gag-specific CD8+ T cell responses in the intestine. Nevertheless, we found that it potentiates otherwise weak intestinal CD8+ T cell responses in nasally primed mice with Gag p24 and cholera toxin adjuvant. Thus, the oral delivery of Salmonella expressing Gag would be utilized in combination with other parenteral vaccine to direct and strengthen intestinal HIV-specific CTL responses.