Pathophysiology of hypertension in the absence of nitric oxide/cyclic GMP signaling

Abstract

The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling system is a well-characterized modulator of cardiovascular function, in general, and blood pressure, in particular. The availability of mice mutant for key enzymes in the NO-cGMP signaling system facilitated the identification of interactions with other blood pressure modifying pathways (e.g. the renin-angiotensin-aldosterone system) and of gender-specific effects of impaired NO-cGMP signaling. In addition, recent genome-wide association studies identified blood pressure-modifying genetic variants in genes that modulate NO and cGMP levels. Together, these findings have advanced our understanding of how NO-cGMP signaling regulates blood pressure. In this review, we will summarize the results obtained in mice with disrupted NO-cGMP signaling and highlight the relevance of this pathway as a potential therapeutic target for the treatment of hypertension.

Figure 1. Nitric oxide (NO) - cGMP signaling in endothelium-dependent relaxation of vascular smooth muscle cells (VSMC)

Endothelial cells (EC) respond to agonist stimulation by increasing intracellular Ca²⁺ concentration and activity of endothelial nitric oxide (NO) synthase (eNOS). Shear stress also leads to eNOS activation via Akt-dependent phosphorylation. NO diffuses into adjacent VSMC and activates soluble guanylate cyclase (sGC), leading to increased cGMP production and protein kinase G I (PKGI) activation. PKGI activation promotes vasorelaxation via multiple mechanisms. PKGI interferes with vasoconstrictor signaling via G protein-coupled receptors (GPCR) by activating regulator of G protein signaling-2 (RGS-2), inhibiting phospholipase C (PLC), and stimulating inositol triphosphate (IP₃) receptor-associated PKG substrate (IRAG), which ultimately leads to inhibition of Ca²⁺ release from the sarcoplasmic reticulum (SR) via the IP₃ receptor (IP₃R). Phosphorylation by PKGI also inhibits phospholamban (PLB), leading to increased Ca²⁺ reuptake into the SR by sarco/endoplasmic reticulum ATPase (SERCA). On the other hand, PKGI interferes with RhoA and rho-associated protein kinase (ROCK)-dependent inhibition of myosin light chain phosphatase (MLCP). Together with a direct activation of MLCP, this leads to increased dephosphorylation of the regulatory light chain of myosin, which promotes vasorelaxation by blocking actin-myosin interaction. PKGI also reduces extracellular Ca²⁺ influx directly by inhibiting the L-type Ca²⁺ channel (LTCC). Activation of the large conductance Ca²⁺-activated K⁺ channel (BK), which can also be directly stimulated by NO, and the ATP-dependent K⁺ channel (K_ATP) cause VSMC hyperpolarization leading to inhibition of the LTCC. ACh: acetylcholine, Bk: bradykinin, Ins: insulin, L-Arg: L-Arginine, MLCK: myosin light chain kinase.