Atrial natriuretic peptide (ANP) regulates blood pressure and volume. Its receptor, the guanylyl cyclase-A (GC-A) is expressed in vascular endothelium and mediates increases in intracellular cyclic GMP (cGMP) levels, but the functional relevance is controversial. Notably, mice with endothelial-restricted GC-A deletion (EC GC-A KO mice) exhibit significant hypervolemia and hypertension, suggesting that ANP regulates transvascular fluid balance via changes in endothelial permeability (J Clin Invest 2005; 115: 1666). To proof this hypothesis, we compared the effect of ANP on microvascular permeability to FITC-labelled albumin (BSA) in wildtype (WT) and GC-A - deficient (GC-A KO) mice instrumented with dorsal skinfold chambers. In WT mice, local superfusion of ANP provoked an increase in FITC- BSA extravasation. This effect was abolished and even reversed in GC-A KO. One possible effect of endothelial cGMP could be the stimulation cGMP-dependent protein kinase I (PKG I) and thereby the phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a protein modulating the actin cytoskeleton. Indeed, incubation of WT primary lung endothelial cells (LEC) with ANP increased intracellular cGMP and phosphorylation of VASP at the PKG I?specific site Ser325. Both responses were totally abolished in GC-A ?deficient LEC.

(supported by SFB 688).