Workgroup Kuhn

    Vascular system permeability

    Endocrine vascular actions of atrial natriuretic peptide (ANP) and its guanylyl cyclase receptor (GC-A) are critically involved in the regulation of arterial blood pressure and blood volume (SFB 688)

    Wen Chen, Birgit Gaßner, Katharina Völker, Michaela Kuhn

    The endocrine actions of the cardiac hormone ANP are critical in the maintenance of arterial blood pressure and volume homeostasis. The main known GC-A-mediated hypovolemic and hypotensive actions of ANP include the following: stimulation of renal function; vasodilatation; increased fluid efflux from the intravascular to the lymphatic system within the spleen; inhibition of the renin-angiotensin-aldosteron (RAA) system by direct actions on juxtaglomerular cells and the adrenal glomerulosa; and central nervous effects that decrease salt appetite and water drinking.

    Within the vascular system the GC-A receptor is densely expressed both in smooth muscle and in endothelial cells. To dissect these vascular actions of ANP in vivo, we inactivated the murine GC-A gene selectively either in smooth muscle cells (SMC) or in endothelia (EC), using Cre-lox technology. Remarkably, smooth muscle-restricted deletion of GC-A in mice completely abolished the direct vasodilating effect of ANP but did not affect resting arterial blood pressure. In contrast, endothelium-restricted GC-A deletion preserved ANP vasodilatation but caused hypervolemic hypertension. Our vital microscopy and MR studies showed that ANP enhances microvascular endothelial macromolecule permeability and thereby shifts the balance of hydrostatic and colloid osmotic forces across capillary walls in favor of moving protein-free fluid from the plasma into interstitial pools. This ultimately decreases intravascular volume and blood pressure. Modulation of endothelial permeability via GC-A may in fact represent one of the physiologically most important actions of ANP.

    In our ongoing research project in Sonderforschungsbereich SFB 688 we are elucidating how ANP modulates transendothelial versus paracellular permeability and which are the distal postreceptor pathways. Our observations support the notion that ANP adjusts caveolae-mediated transcytosis of albumin in microvessels of the skin and skeletal muscle to maintain intravascular fluid volume homeostasis (see following scheme).

    Reference List

    Lopez JM, Garbers DL, Kuhn M (1997) The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 272:23064–23068.

    Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B, Hammer B, Herz J, Kuhn M (2002). Smooth muscle - selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci USA 99:7142-7147.

    Sabrane K, Gambaryan S, Brandes R, Holtwick R, Kuhn M (2003) Increased sensitivity to endothelial nitric oxide/NO contributes to arterial normotension in mice with vascular smooth muscle-selective deletion of the ANP-receptor. J Biol Chem 278:17963–17968.

    Bulut D, Potthast R, Hanefeld C, Schulz T, Kuhn M, Mügge A (2003) Impaired vasodilator responses to Atrial Natriuretic Peptide in Essential Hypertension. Eur J Clin Invest 33:567– 573.

    Steinmetz M, Potthast R, Voß M, Sabrane K, Kuhn M (2004) Diverging vasorelaxing effects of C-type natriuretic peptide in renal resistance arteries and aortas of GC-A deficient mice. Regul Peptides 119:31-37.

    Holtwick R, Skryabin M, Fabritz L, Kruse M, Kuhn M (2004) Chronic hypervolemia and hypertension in mice with systemic inactivation of the (floxed) guanylyl cyclase-A gene by MHC-Cre - mediated germline recombination. Genesis 39:288-298.

    Sabrane K, Kruse MN, Fabritz L, Zwiener M, Zetsche B, Skryabin BV, Baba HA, Yanagisawa M, Kuhn M (2005) Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide. J Clin Invest 115:1666-1674.

    See accompanying Editorial from Curry FR. Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume. J Clin Invest 2005;115:1458-1461.

    Schreier B, Börner S, Völker K, Gambayran S, Schäger SC, Kuhlencordt P, Gaßner B, Kuhn M (2008) The heart communicates with the endothelium through the guanylyl cyclase-A receptor: acute handling of intravascular volume in response to volume expansion. Endocrinology 149:4193-4199.

    Sabrane K, Kruse MN, Gazinski A, Kuhn M. (2009) Chronic endothelium-dependent regulation of arterial blood pressure by ANP: role of nitric oxide and endothelin-1. Endocrinology 150:2382-2387.

    Curry FR, Rygh CB, Karlsen T, Wiig H, Adamson RH, Clark JF, Lin YC, Gassner B, Thorsen F, Moen I, Tenstad O, Kuhn M, Reed RK. (2010) Atrial natriuretic peptide modulation of albumin clearance and contrast agent permeability in mouse skeletal muscle and skin: role in regulation of plasma volume. J Physiol 588:325-339.