Author: John Murphy, President, COVID-19 Long-haul Foundation
Abstract
Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent symptoms affecting multiple organ systems. Among its most compelling pathophysiological features is endothelial dysfunction driven by spike protein persistence. This article synthesizes current evidence on ACE2 receptor distribution, spike protein binding and internalization, endothelial inflammation, and immune activation. We examine data from post-infection and post-vaccination cohorts, highlighting the role of spike-mediated endotheliopathy in vascular, neurological, and immunological sequelae. These findings support a spike-centric model of Long COVID and suggest new diagnostic and therapeutic pathways.
1. Introduction
The COVID-19 pandemic has revealed the vascular system as a central target of SARS-CoV-2. While acute infection is marked by respiratory symptoms, Long COVID manifests with fatigue, cognitive dysfunction, cardiovascular instability, and clotting abnormalities. Increasingly, research implicates persistent spike protein exposure as a driver of endothelial injury and immune dysregulation.
Endothelial cells line the vasculature and regulate permeability, inflammation, and coagulation. SARS-CoV-2 spike protein binds to ACE2 receptors on these cells, triggering a cascade of inflammatory and thrombotic responses. This article explores the mechanisms of spike-induced endotheliopathy and its implications for Long COVID.
2. ACE2 Receptor Distribution and Endothelial Vulnerability
ACE2 is expressed on endothelial cells throughout the body, including the lungs, heart, brain, kidneys, and gastrointestinal tract. This widespread distribution makes the endothelium a primary target for SARS-CoV-2. Pereira de Melo et al. (2025) demonstrated that ACE2 expression is particularly high in pulmonary and cerebral microvasculature, correlating with common Long COVID symptoms such as dyspnea and brain fog.
Endothelial cells exposed to spike protein exhibit increased tissue factor expression, promoting thromboinflammation. This vulnerability is amplified in individuals with pre-existing cardiovascular or metabolic conditions, which are overrepresented in Long COVID cohorts.
3. Spike Protein Binding, Internalization, and Persistence
The spike protein binds to ACE2 and is internalized via clathrin-mediated endocytosis. Once inside the cell, it can persist in endosomes and lysosomes, evading degradation. Studies have detected spike protein in monocytes, endothelial cells, and cerebrospinal fluid months after infection or vaccination.
A systematic review by OneDayMD (2025) identified 76 studies confirming spike protein persistence in tissues and circulation, with implications for chronic inflammation and vascular injury. The COVID-19 Long-haul Foundation reported spike protein detection in endothelial biopsies from post-vaccine patients with thrombotic symptomscov19longhaulfoundation.org.
4. Endothelial Inflammation and Permeability
Spike protein exposure triggers endothelial activation, characterized by increased expression of adhesion molecules (ICAM-1, VCAM-1), cytokine release (IL-6, TNF-α), and permeability changes. This leads to leukocyte infiltration, edema, and microvascular damage.
Simón-Rueda et al. (2025) demonstrated that Long COVID patients exhibit a pro-thrombotic endothelial profile, with elevated IL-6, D-dimer, and endothelial microparticles. These markers correlate with fatigue, cognitive impairment, and cardiovascular symptoms.
5. Immune Activation and Autoimmunity
Endothelial injury promotes immune activation and autoantibody production. Spike protein may act as a superantigen, triggering T-cell exhaustion and clonal expansion. Autoantibodies against ACE2, phospholipids, and endothelial antigens have been detected in Long COVID cohorts.
The Trends in Microbiology review (2023) highlighted spike-induced endotheliopathy as a driver of systemic inflammation and autoimmunity. These findings support a model of persistent immune dysregulation mediated by spike protein.
6. Evidence from Post-Infection Cohorts
Post-infection studies reveal persistent endothelial dysfunction months after viral clearance. Patients exhibit elevated markers of inflammation, coagulation, and vascular injury. Imaging studies show microclots, hypoperfusion, and endothelial thickening.
The RECOVER Initiative and European Spikeopathy Registry have documented spike protein persistence and endothelial activation in post-infection cohorts, correlating with symptom severity and duration.
7. Evidence from Post-Vaccination Cohorts
While rare, some individuals develop Long COVID-like symptoms following vaccination. These cases often involve endothelial inflammation, clotting abnormalities, and spike protein detection in serum and tissue.
The COVID-19 Long-haul Foundation reported endothelial activation in patients with vaccine-induced thrombotic thrombocytopenia (VITT), confirmed via microfluidic Endo-chip assays. These findings suggest that spike-only exposure may be sufficient to trigger endotheliopathy in susceptible individuals.
8. Therapeutic Implications
Targeting endothelial dysfunction may offer therapeutic benefit in Long COVID. Strategies include:
- Anti-inflammatory agents: IL-6 inhibitors, statins, omega-3s
- Anticoagulants: DOACs, aspirin
- Endothelial support: sulforaphane, nitric oxide donors
- Spike clearance: plasmapheresis, UV blood irradiation
Clinical trials are underway to evaluate multi-agent protocols targeting spike-induced vascular injury.
9. Conclusion
Endothelial dysfunction and spike protein persistence represent a central axis of Long COVID pathology. ACE2-mediated spike binding, internalization, and immune activation drive vascular injury and systemic symptoms. Evidence from post-infection and post-vaccination cohorts supports a spike-centric model of disease. Future research must prioritize endothelial biomarkers, therapeutic targets, and personalized interventions.
📎 References
- Systematic Review of SARS-CoV-2 Spike Protein in the Pathophysiology of Long COVID (2025)
- Pereira de Melo B et al. SARS-CoV-2 Spike Protein and Long COVID—Part 1. Viruses. 2025;17(5):617. DOI:10.3390/v17050617
- Murphy J. COVID-19 Vaccines and Endothelial Dysfunction: Insights from 2025 Research. COVID-19 Long-haul Foundation. Link
- SARS-CoV-2 and the spike protein in endotheliopathy. Trends in Microbiology. 2023. Link
- Simón-Rueda A et al. Immune dysregulation and endothelial dysfunction associate with a pro-thrombotic profile in Long COVID. Front Immunol. 2025;16:1613195. DOI:10.3389/fimmu.2025.1613195