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Vascular endothelial growth factor A (VEGFA) was originally discovered as vascular permeability factor (VPF). Its organ-specific regulation of the vascular barrier is mediated by the receptor tyrosine kinase VEGFR2 and becomes dysregulated in inflammatory diseases. Excessive vascular leakage causes edema and aggravates inflammation, thereby promoting the progression of conditions such as retinopathy and cancer. Studies using mouse models with endothelial-specific deletion or overexpression of signaling components downstream of VEGFA–VEGFR2 have provided important mechanistic insights. These studies have identified distinct Src family kinases (SFKs) as regulators of transient gaps at endothelial adherens junctions: Src promotes gap opening, whereas Yes1 facilitates gap closure. In contrast, Fyn, another SFK activated downstream of VEGFA, is required for maintaining balanced endothelial survival/apoptosis. Modestly elevated VEGFA levels in mice preserve vascular density and perfusion during aging; however, the mode and cellular source of VEGFA delivery are critical. Indeed, endothelial overexpression of either VEGFA or Fyn, driven by the Cdh5 (VE-cadherin) promoter, produces organ-specific vascular malformations. Thus, vascular homeostasis depends on precisely calibrated VEGFA–VEGFR2 signaling regulation barrier function and endothelial survival.