SARS-CoV-2 engages ACE2 for cell entry, perturbing the counter-regulatory ACE2/Ang-(1-7)/Mas axis and shifting the renin angiotensin system toward ACE/Ang II/AT1 signaling, with a concomitant reduction in nitric oxide (NO) bioavailability. NO sits at the crossroads of these pathways, acting both as an antiviral modulator of spike-ACE2 interactions and as a downstream mediator of Mas-dependent endothelial protection. This review summarizes evidence on NO across three layers: (i) viral entry (S nitrosylation of spike/ACE2, protease modulation), (ii) cardiovascular comorbidities (hypertension, obesity, diabetes) where ACE2 downregulation impairs endothelial NO synthase (eNOS)-dependent NO production and promotes thrombosis and microvascular dysfunction, and (iii) neurovascular/ neurodegenerative sequelae, in which renin-angiotensin-aldosterone system (RAAS) dysregulation along with imbalance between protective eNOS/nNOS and inflammatory iNOS fosters blood-brain barrier disruption, microthrombosis, and cognitive impairment. Shared mechanisms - endotheliitis, microvascular dysfunction, and neuroinflammation may explain convergent risks for cardiac injury and cognitive decline in long COVID-19. Putative therapeutic strategies may include restoring physiological NO (via Mas agonism, Ang-(1-7), inhibition of Ang 1-7 degradation and recombinant ACE2), pulmonary-selective inhaled NO, hybrid S nitrosylated agents, and selective attenuation of iNOS/peroxynitrite alongside endothelial support. Targeted modulation - enhancing eNOS/nNOS while constraining iNOS offers a unified framework to mitigate both cardiovascular and neurodegenerative consequences of COVID-19.

Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Bratislava Slovak Republic

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