Objective—Angiotensin II (Ang II) and tumor necrosis factor (TNF)- levels increase endothelial permeability, and we hypothesized that adiponectin suppressed these responses in a cAMP-dependent manner.

Methods and Results—The effect of adiponectin on transendothelial electric resistance (TEER) and diffusion of albumin through human umbilical vein and bovine aortic endothelial cell monolayers induced by Ang II (100 nmol/L) or TNF (5 ng/mL) was measured. Treatment with the globular domain of adiponectin (3 µg/mL) for 16 hours abrogated the adverse TEER effect of TNF (-35 versus -12 /cm² at 45 minutes, P<0.05) and Ang II (-25 versus -5 /cm² at 45 minutes, P<0.01) and partially suppressed the increased diffusion of albumin with Ang II (40% versus 10% change, P<0.05) or TNF (40% versus 20% change, P<0.05). Full-length adiponectin also suppressed Ang II–induced monolayer hyperpermeability. Adiponectin treatment also suppressed Ang II–induced increased actin stress fiber development, intercellular gap formation, and -tubulin disassembly. Adiponectin increased cAMP levels, and its effects were abrogated by inhibition of adenylyl cyclase or cAMP-dependent protein kinase signaling.

Conclusions—Adiponectin protects the endothelial monolayer from Ang II or TNF-induced hyperpermeability by modulating microtubule and cytoskeleton stability via a cAMP/ PKA signaling cascade.