James Choi

Introduction: Hypertension is considered higher than normal blood pressure that progressively develops due to underlying diseases such as diabetes or obesity or through poor lifestyle choices in diet and lack of exercise. It is also the most important contributor to cardiovascular diseases (CVDs) such as heart failure, myocardial infarction, and angina, with projected prevalence of over 1.5 billion people worldwide by 2025¹. Investigations to understand the connection between hypertension and CVD are ongoing, and one forefront to control hypertension is through the regulation of tone of resistance vessels in the microcirculation by natriuretic peptides. Recent evidence has shown that C-type natriuretic peptide (CNP) is released by the vascular endothelium and regulates vascular resistance². However, the mechanism of action of and cellular target for CNP remain elusive³. One study has demonstrated that a major target resides in the capillary pericytes, which relax in response to CNP by activation of the guanylyl cyclase B receptor (GC-B) and subsequent elevation of intracellular cGMP⁴. The findings indicate a potential therapeutic target to regulate systemic hypertension. Methods: Mice with knockout of the GC-B gene in endothelial cells, smooth muscle cells (SMCs), or pericytes were individually infused with CNP to understand the sensitivities of each target tissue to CNP. Hemodynamics in vivo and measurement of cGMP in cultured vascular cells were employed to understand the CNP/GC-B/cGMP signaling mechanism in regulating microvascular tone and blood pressure at each of the tissues mentioned⁴. Results: Vasodilatory effects of CNP increased towards small-diameter arterioles and capillaries. CNP reversed endothelin-1 (ET-1)-induced constriction of precapillary arterioles and capillaries but had minimal effect on the response of proximal arterioles. Vasodilatory effects of CNP were abolished in mice lacking GC-B in microvascular SMCs and pericytes, but they were preserved in GC-B knockout in endothelial cells. The former effect led to increased peripheral resistance and chronic arterial hypertension. CNP increased the intracellular cGMP levels in cultured pericytes from control mice but not from GC-B knockout mice, indicating that CNP binding to GC-B enacts vasodilatory effects through a GC-B/cGMP signaling pathway⁴. Conclusions: Studies have demonstrated that CNP modulates peripheral vascular tone through vasodilatory effects with cellular targets in the microcirculation. Its ability to reverse ET-1-induced constriction and elevate cGMP through GC-B in pericytes shows promise in targeted therapy for hypertension. The discovery indicates possible therapeutic intervention using synthetic CNP mimickers to specifically target the microcirculation to control hypertension, thereby preventing CVD.

1. Sarzani R, Spannella F, Giulietti F, Balietti P, Cocci G, Bordicchia M. Cardiac Natriuretic Peptides, Hypertension and Cardiovascular Risk. High Blood Press Cardiovasc Prev. 2017;24(2):115-126. doi:10.1007/s40292-017-0196-1
2. Nakao K, Kuwahara K, Nishikimi T, et al. Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity. Hypertension. 2017;69(2):286-296. doi:10.1161/HYPERTENSIONAHA.116.08219
3. Vinnakota S, Chen HH. The Importance of Natriuretic Peptides in Cardiometabolic Diseases. J Endocr Soc. 2020;4(6):bvaa052. doi:10.1210/jendso/bvaa052
4. Špiranec K, Chen W, Werner F, et al. Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure. Circulation. 2018;138(5):494-508. doi:10.1161/CIRCULATIONAHA.117.033383