Perivascular Macrophages Convert Physical Wound Signals Into Rapid Vascular Responses

Leukocytes detect distant wounds within seconds to minutes, which is essential for effective pathogen defense, tissue healing, and regeneration. Blood vessels must detect distant wounds just as rapidly to initiate local leukocyte extravasation, but the mechanism behind this immediate vascular response remains unclear. Using high-speed imaging of live zebrafish larvae, we investigated how blood vessels achieve rapid wound detection. We monitored two hallmark vascular responses: vessel dilation and serum exudation. Our experiments—including genetic, pharmacologic, and osmotic perturbations, along with chemogenetic leukocyte depletion—revealed that the cPla 2 nuclear shape sensing pathway in perivascular macrophages converts a fast (∼50 μm/s) osmotic wound signal into a vessel-permeabilizing, 5-lipoxygenase (Alox5a) derived lipid within seconds of injury. These findings demonstrate that perivascular macrophages act as physicochemical relays, bridging osmotic wound signals and vascular responses. By uncovering this novel type of communication, we provide new insights into the coordination of immune and vascular responses to injury.