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).
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