{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:51:15Z","timestamp":1789001475297,"version":"build-2803163510"},"reference-count":81,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>SARS-CoV-2 engages ACE2 for cell entry, perturbing the counter-regulatory ACE2\/Ang-(1\u20137)\/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\u2013brain 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\u20137), 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.<\/jats:p>","DOI":"10.33549\/physiolres.935729","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T13:44:30Z","timestamp":1768225470000},"page":"S171","source":"Crossref","is-referenced-by-count":2,"title":["Nitric Oxide at the Nexus of ACE2 Biology and COVID-19: Implications for Cardiovascular and Neurodegenerative Comorbidities"],"prefix":"10.33549","author":[{"given":"O","family":"Pechanova","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05ra1x588","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Normal and Pathological Physiology of the Slovak Academy of Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Paulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"1.\tJackson CB, Farzan M, Chen B, Choe H. 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