Abstract 12953: Vascular Dysfunction and Hypertension in Endothelium-Specific C-Type Natriuretic Peptide Knockout Mice
Background: C-type natriuretic peptide (CNP) is a paracrine mediator that possesses a unique vaso- and cardio- protective pharmacodynamic profile. CNP also contributes to endothelium-derived hyperpolarising factor (EDHF) responses in vitro intimating it plays a role in regulating local blood flow and systemic blood pressure. Herein, we have generated a novel conditional knockout mouse with selective deletion of this natriuretic peptide from vascular endothelial cells to determine whether CNP plays a fundamental cardiovascular homeostatic role in vivo.
Methods: Endothelial cell-specific CNP knockout (ecCNP KO) mice were generated by flanking exons 1 & 2 of the Nppc gene (contains the entire peptide coding sequence) with loxP sites and crossing of these animals with endothelium-specific (Tie2) Cre-recombinase expressing mice (both C57BLK6 background); littermate controls were used in all studies. Isolated conduit (aortic) and resistance (mesenteric) vessels were used to test functional reactivity in wild type (WT) and ecCNP KO mice in vitro. The effect of genotype on mean arterial blood pressure (MABP) was determined by implantation of radiotelemetric probes into the common carotid.
Results: Mesenteric arteries from ecCNP KO mice were significantly less sensitive to the vasodilator ACh compared to WT mice (pEC50: WT=7.2±0.20 vs. KO=6.5±0.33; P<0.05; n=6). EDHF responses were also attenuated in ecCNP KO vessels (pEC50: WT=6.93±0.22 vs. KO=5.96±0.29; P<0.05; n=6). In contrast to resistance arteries, the potency of ACh was unaltered in ecCNP KO aortae (pEC50: WT=7.52±0.04 vs. KO=7.54±0.08; n=6). Furthermore, genotype did not influence vasoconstrictor or endothelium-independent vasodilator concentration-response curves in the aorta or mesentery. MABP was significantly higher in ecCNP KO mice (MABP: WT=106±1mmHg vs. KO=115±1mmHg. P<0.001; n=8). ecCNP KO mice also exhibited enhanced blood pressure variability (CV: WT=14.4% vs. KO=18.4% P<0.05; n=8) and a lower heart rate (WT=600±3bpm vs. KO=569±4bpm; P<0.001; n=8).
Conclusions: These findings demonstrate that endothelial CNP plays a significant physiological role in the regulation of resistance artery function, EDHF bioactivity and maintenance of systemic blood pressure.
- © 2010 by American Heart Association, Inc.