ADAM 17 Regulates S1PR1 Surface Expression by its Ectodomain Shedding thereby Disrupting Endothelial Barrier Function

Acute lung injury (ALI) is characterized by excessive transendothelial leakage of protein rich fluid and infiltration of leukocytes into the alveolar space. Sphingosine phosphate receptor 1 (S1PR1), a G protein coupled receptor abundantly present in endothelial cells (ECs), upon binding to sphingosine 1 phosphate (S1P) maintains EC barrier function and inhibit leukocyte infiltration into the interstitium thereby preventing ALI. However, it is unclear whether alteration of S1PR1 expression sets the stage for induction of ALI. ADAM belongs to family of disintegrin and metalloproteinase family of enzymes which induces the shedding of the growth factor receptors and cell surface proteins. We show here that activation of ADAM in human pulmonary arterial endothelial cells (HPAECs) using phorbol 12-myristate 13-acetate (PMA) degraded S1PR1 and these cells failed to enhance endothelial barrier function with S1P. Among different ADAMs, ADAM 17 and ADAM 10 are known to be induced upon ALI but whether they alter S1P...