Vasoprotective effects of LPA inhibit vascular injury caused by SARS-CoV-2 infection

Vasculitis and vascular injury are induced in COVID-19 patients, suggesting an association with multi-organ failure and sequelae. Vascular protection following SARS-CoV-2 infection is important since COVID-19 severity is linked to these vascular injuries. Infection of vascular endothelial cells with SARS-CoV-2 causes vascular endothelial cell injury, leading to disruption of vascular barrier function, activation of coagulation pathways, and extravasation of inflammatory cells. We focused on the vasoprotective effects of LPA, a lipid mediator with diverse activities, and investigated whether it could be a novel therapeutic target for COVID-19. Three-dimensional cultures of various human vascular endothelial cells to form luminal structures showed increased expression of LPA4 receptors and entry receptors for SARS-CoV-2 infection, mimicking blood vessels in vivo. Validation using this culture system showed that LPA attenuated SARS-CoV-2 infection-induced vascular destruction and activation of inflammatory signaling. In experiments with infected animals, LPA administration also protected blood vessels and suppressed inflammation and vascular damage in lung tissue. Activation of LPA4 receptor signaling in vascular endothelial cells is expected to be an effective therapeutic target to prevent vascular injury in COVID-19.