# Nitric Oxide at the Nexus of ACE2 Biology and COVID-19: Implications for Cardiovascular and Neurodegenerative Comorbidities

## TL;DR

This paper explores how nitric oxide (NO) is involved in the biology of ACE2 and its role in the cardiovascular and neurological effects of COVID-19.

## Contribution

The paper introduces a unified framework for targeting nitric oxide pathways to mitigate both cardiovascular and neurodegenerative impacts of COVID-19.

## Key findings

- Nitric oxide (NO) is a key mediator in ACE2 biology and SARS-CoV-2 infection.
- ACE2 downregulation reduces NO production, contributing to cardiovascular and neurodegenerative complications.
- Therapeutic strategies to restore NO may help reduce microvascular dysfunction and cognitive decline in long COVID-19.

## Abstract

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.