Vinculin strengthens the endothelial barrier during vascular development.

Remodelling of cell-cell junctions is crucial for proper tissue development and barrier function. The cadherin-based adherens junctions anchor via ß-catenin and α-catenin to the actomyosin cytoskeleton, together forming a junctional mechanotransduction complex. Tension-induced conformational changes in the mechanosensitive α-catenin protein induce junctional vinculin recruitment. In endothelial cells, vinculin protects the remodelling of VE-cadherin junctions. In this study, we have addressed the role of vinculin in endothelial barrier function in the developing vasculature. In vitro experiments, using endothelial cells in which α-catenin was replaced by a vinculin-binding-deficient mutant, showed that junctional recruitment of vinculin promotes endothelial barrier function. To assess the role of vinculin within blood vessels in vivo, we next investigated barrier function in the vasculature of vcl knockout zebrafish. In the absence of vinculin, sprouting angiogenesis and vessel perfusion still occurred. Intriguingly, the absence of vinculin made the blood vessels more permeable for 10 kDa dextran molecules but not for larger tracers. Taken together, our findings demonstrate that vinculin strengthens the endothelial barrier and prevents vascular leakage in developing vessels.

Trigeminovascular effects of propranolol in men and women, role for sex steroids.

OBJECTIVE: Assess whether propranolol modulates the trigeminovascular system in both men and women. METHODS: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to Tmax ) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2-1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20-39 years old). RESULTS: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. INTERPRETATION: Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system.