Dysregulation of Nitric Oxide/cGMP Pathway: A Pathological Cascade in Vascular Dysfunction
Creators: name: Shoaib, Minahil
name: Khaliq, Hafiz Muhammad Haseeb
name: Baig, Deeba
Publisher: name: Zenodo OPENAIRE indexed Google Scholar
Year: 2024
Subjects: NO/cGMP pathway
Vascular Dysfunction
Pathology
Cell signaling
pulmonary hypertension
Alzheimer's disease

description: ABSTRACT

Nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) signaling are integral to regulating diverse physiological processes, particularly within cardiovascular and neuronal systems. The NO/cGMP pathway governs vascular relaxation and blood pressure regulation with help of interactions between endothelial and smooth muscle cells. Dysregulation of this pathway contributes to endothelial dysfunction and is implicated in conditions such as pulmonary hypertension, atherosclerosis, and cardiac hypertrophy. Additionally, aberrations in NO/cGMP signaling are implicated in neurodegenerative diseases like Alzheimer's disease, where NO-mediated neuronal cell death and cognitive impairment occur.  This review delves into the complex mechanisms underlying NO/cGMP signaling in both physiological and pathological contexts. In endothelial cells, NO generated via endothelial nitric oxide synthase (eNOS) triggers soluble guanylyl cyclase (sGC) activation in vascular smooth muscle cells, culminating in cGMP-mediated vasodilation. Conversely, disruptions in NO production and cGMP levels contribute to endothelial dysfunction and vascular pathologies. In neuronal cells, NO/cGMP signaling modulates synaptic plasticity and memory formation, yet deviations from this pathway lead to neurodegenerative conditions such as Alzheimer's disease.  Comprehending the multifaceted roles of NO/cGMP signaling in health and disease is imperative for developing targeted pharmacotherapies. Novel drug targets encompass NO-donating hybrid medications, CNS-targeting sGC stimulators/activators, and selective PDE inhibitors, all aimed at modulating NO/cGMP pathways to preserve cardiovascular and neuronal health. 

Keywords: NO/cGMP pathway, Vascular Dysfunction, Pathology, Cell signaling, pulmonary hypertension, Alzheimer’s disease



INTRODUCTION


Nitric oxide/cGMP signaling involves the endogenous pathway in which nitric oxide is produced from L-arginine by nitric oxide synthase present in endothelial cells of pulmonary system. This nitric oxide then diffuses to nearby vascular smooth muscle cells and carries out a signaling cascade to activate intracellular guanylyl cyclase which will do relaxation of smooth muscle cells present in blood vessels and controls the blood pressure. Guanylyl cyclase receptor present in smooth muscle cell surface has ferrous containing heme group in its active site due to which it exhibits high affinity to bind with nitric oxide. Apart from that, NO/cyclic-GMP signaling is also involved in leukocyte adhesion, synaptic plasticity, inhibiting aggregation of blood platelets. 



RELAXATION OF PULMONARY VSMCs (VASODILATION)


This signaling pathway starts when ligand i.e., acetylcholine, bradykinin, histamine binds to N-terminal of ligand specific G-protein coupled receptors which are seven trans-membrane proteins present in pulmonary endothelial cells. Ligand binding to receptor induces a change in conformation of GPCR which allows the inactive heterotrimeric G-protein (bounded to GDP) to bind with the C-terminal of ligand specific GPCR (Joyce C at al., 2019). Another protein guanine nucleotide exchange factor removes the GDP and attach GTP to activate the G-protein. This activated G-protein (bounded to GTP) then dissociates into α and βγ subunits. The Gαq subunit of G-protein activates another protein i.e., Phospholipase Cβ to cleave the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into secondary signaling molecules i.e., inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). DAG activates another enzyme i.e., protein kinase C to phosphorylate the MAP kinases and other substrates to trigger cellular proliferation (Berridge et al., 2014).

IP3 diffuses from cytoplasmic membrane into the endoplasmic reticulum membrane to bind with IP3-gated calcium channels and triggers the Ca2+ mobilization, thus releasing the calcium ions from lumen of endoplasmic reticulum. The released calcium ions bind to a calcium sensor i.e., calmodulin. This Ca2+/calmodulin complex then activates the Ca2+/calmodulin-dependent kinase (CaM kinase). This enzyme phosphorylates the endothelial nitric oxide synthase and activates it. Activated eNOS produce nitric oxide from L-arginine and oxygen as follows.

L-Arginine + oxygen + NADPH 🡪 Citrulline + Nitric oxide

The nitric oxide produced in endothelial cells diffuses into nearby pulmonary vascular smooth muscle cells and binds to NO receptors (sGC receptor) present in SMC. This leads to activation of an enzyme i.e., guanylyl cyclase that will hydrolyze GTP to cGMP and phosphate molecules (PPi). Cyclic-GMP activates protein kinase G (PKG) that will phosphorylate downstream signaling proteins to cause relaxation of smooth muscle cells present in blood vessels (joyce C at al., 2019). PKG phosphorylates and activates the Rho protein. Activated RhoA protein further stimulates the Rho-associated protein kinase (ROCK) which catalyzes the phosphorylation and inactivation of myosin light chain phosphatase (MLCP). When MLCP is activated i.e., non-phosphorylated, it catalyzes the dephosphorylation of MLC and promotes relaxation of smooth muscle cells. On the other hand, cGMP also inhibits GMP phosphodiesterase to prevent conversion of cGMP to GMP. Due to increased cGMP, there will be vasodilation of muscle arteries leading to increased blood flow and lowers the blood pressure (as shown in Figure 1). 

 



PATHOLOGICAL NITRIC OXIDE (NO)/cGMP SIGNALING PATHWAYS

Alterations in production of nitric oxide cause endothelial dysfunction which leads to diseases in cardiac cells, muscle cells 

and nerve endings. cGMP levels are disrupted in pulmonary hypertension, atherosclerosis, diabetes etc. Imbalance in


vasodilators and vasoconstrictors cause endothelium dysfunction, thus resulting in cardiovascular diseases like cardiac hypertrophy, hypertension and congestive heart failure.  Overexpression of nitric oxide plays an important role in neurodegenerative diseases, septic shock and ischemia-reperfusion.