Vascular Pathogenesis in Acute and Long COVID: Current Insights and Therapeutic Outlook

Abstract

Long coronavirus disease 2019 (COVID-19)-a postacute consequence of severe acute respiratory syndrome coronavirus 2 infection-manifests with a broad spectrum of relapsing and remitting or persistent symptoms as well as varied levels of organ damage, which may be asymptomatic or present as acute events such as heart attacks or strokes and recurrent infections, hinting at complex underlying pathogenic mechanisms. Central to these symptoms is vascular dysfunction rooted in thrombotic endothelialitis. We review the scientific evidence that widespread endothelial dysfunction (ED) leads to chronic symptomatology. We briefly examine the molecular pathways contributing to endothelial pathology and provide a detailed analysis of how these cellular processes underpin the clinical picture. Noninvasive diagnostic techniques, such as flow-mediated dilation and peripheral arterial tonometry, are evaluated for their utility in identifying ED. We then explore mechanistic, cellular-targeted therapeutic interventions for their potential in treating ED. Overall, we emphasize the critical role of cellular health in managing Long COVID and highlight the need for early intervention to prevent long-term vascular and cellular dysfunction.

Fig. 1

COVID-associated endothelial dysfunction and endothelialitis. Schematic representation of COVID-associated ED and endothelialitis. (1) Under pathological conditions, Type I and Type II endothelial activation—together with endothelial cell injury, such as endothelial cell apoptosis and necrosis—are all involved in ED. (2) Endothelial activation promotes the production of various cytokines, chemokines, and other biomolecules that are involved in coagulation and the immune response. (3) Viral persistence may contribute to ongoing endothelial inflammation or ED in Long COVID. (4) After invasion of the endothelial cells by the virus, P-selectin, TF, ICAM1, VCAM1, and PAI-1 are expressed on these cells and ultra-large VWF multimers are also released. (5) The downregulation of ACE2 favors ED and leads to (6) a dysregulated local RAS with increased levels of Angiotensin II. (7) Capillary rarefication (indicating an inflammatory response) has also been noted in patients suffering from Long COVID. (8) Platelet hyperactivation is a key feature of a hypercoagulable state and has also been noted as a prominent feature in the pathobiology of acute infection and Long COVID. Created with BioRender.com. ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; ED, endothelial dysfunction; ICAM1, intercellular adhesion molecule 1; PAI-1, plasminogen activator inhibitor 1; RAS, renin–angiotensin system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TF, tissue factor; VCAM1, vascular cell adhesion molecule 1; VWF, Von Willebrand factor.

Fig. 2

COVID-19-associated endothelialitis and hypercoagulability. Factors contributing to COVID-19-induced endothelialitis and hypercoagulability including platelet activation, cytokine release by endothelial cells from SARS-CoV-2 S1 subunit stimulation, and NF-κB activation leading to inflammation. Long-term effects include capillary rarefication and persistent fibrinaloid microclots, which may impair microcirculation and oxygen delivery. Created with BioRender.com. ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; ICAM1, intercellular adhesion molecule 1; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor kappa B; PAI-1, plasminogen activator inhibitor 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane protease serine 2 receptors; VCAM1, vascular cell adhesion molecule 1.

Fig. 3

CT scans in acute COVID-19 lung disease. The scans are characterized by vascular phenomena in a vascular-dependent distribution. The airways are not inflamed (no bronchial wall thickening or mucous secretion plugging). ( A ) Peripheral GGOs (arrows) and consolidation (open arrows) accompanied by dilated pulmonary vessels (arrowheads). ( B ) GGOs accompanied by dilated vessels. ( C ) Peripheral lung GGO and dilated vessel. ( D ) Peripheral wedge-shaped areas of GGO/consolidation with dilated vessels indicating pulmonary vascular congestion. CT, computed tomography; COVID-19, coronavirus disease 2019; GGO, ground-glass opacification(s).

Fig. 4

Special investigations to consider in individuals with Long COVID. Techniques such as (1) flow-mediated dilation (FMD) can be used to confirm ED in subjects suffering from Long COVID. (The brachial artery is measured during three conditions [A] at baseline, after at least 10 minutes supine rest; [B] during reactive hyperemia—induced by inflation of a sphygmomanometer cuff to 250 mm Hg for 5 minutes around the forearm and then deflation—and [C] after administration of sublingual nitroglycerin. A linear array, high resolution ultrasound transducer is used to provide B-mode images of the target vessel, proximal to the forearm cuff.) (2) Peripheral arterial tonometry can also be used to confirm ED. Perfusion-based imaging, such as SPECT, VQ, or DECT (3) can detect vasculopathic and thrombotic phenomena in individuals with persistent respiratory symptoms. (4) Nailfold video capillaroscopy is a useful technique to detect microvascular abnormalities. Created with Biorender.com. COVID, coronavirus disease; DECT, dual-energy computed tomography; ED, endothelial dysfunction; FMD, flow-mediated dilation; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography; VQ, ventilation/perfusion scans.