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In healthy blood vessels, albumin crosses the endothelium to leave the circulation by transcytosis. However, little is known about the regulation of albumin transcytosis or how it differs in different tissues; its physiological purpose is also unclear. Using total internal reflection fluorescence microscopy, we quantified transcytosis of albumin across primary human microvascular endothelial cells from both lung and skin. We then validated our in vitro findings using a tissue-specific knockout mouse model. We observed that albumin transcytosis was saturable in the skin but not the lung microvascular endothelial cells, implicating a receptor-mediated process. We identified the scavenger receptor CD36 as being both necessary and sufficient for albumin transcytosis across dermal microvascular endothelium, in contrast to the lung where macropinocytosis dominated. Mutations in the apical helical bundle of CD36 prevented albumin internalization by cells. Mice deficient in CD36 specifically in endothelial cells exhibited lower basal permeability to albumin and less basal tissue edema in the skin but not in the lung. Finally, these mice also exhibited a smaller subcutaneous fat layer despite having identical total body weights and circulating fatty acid levels as wild-type animals. In conclusion, CD36 mediates albumin transcytosis in the skin but not the lung. Albumin transcytosis may serve to regulate fatty acid delivery from the circulation to tissues.

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5 The abbreviations used are: LPS, lipopolysaccharide; TNF, tumor necrosis factor; LBP, LPS-binding protein; TLR4, Toll-like receptor 4; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-␤; IFN, interferon; IL, interleukin; PMA, phorbol 12-myristate 13-acetate; med, medium control; SEAP, secreted embryonic alkaline phosphatase; sCD14, soluble CD14; FBS, fetal bovine serum; DIC, differential interference contrast.