A vascular mechanism may explain the persistence of COVID-19 symptoms and their greater impact, especially in women

A research team led by IGTP, in collaboration with IR Sant Pau and ISGlobal, identifies a protein as a central element in long COVID and highlights differences according to sex and hormonal status.

Long COVID affects millions of people worldwide and is characterised by symptoms that can last for months or even years after the initial infection, such as fatigue, neurological, muscular and respiratory problems. Although women tend to experience milder COVID-19, they are more likely to develop persistent symptoms.

Researchers from GCAT|Genomes for Life, a strategic project of the Germans Trias i Pujol Research Institute (IGTP), have led a study in collaboration with teams from Institut de Recerca Sant Pau (IR Sant Pau) and the Barcelona Institute for Global Health (ISGlobal), with the aim of identifying molecular pathways related to symptom persistence and gaining a better understanding of the underlying mechanisms.

The study was based on the COVICAT cohort, created in 2020 from the GCAT project and coordinated with ISGlobal teams to monitor the impact of COVID-19. Five years on, the cohort remains active and has enabled the analysis of blood samples from 171 participants using high-resolution proteomics technology. The scientists studied nearly 1,400 proteins related to inflammation and cardiovascular health, comparing levels between individuals with and without long COVID, and among pre- and postmenopausal women. Using advanced statistical models and network analysis, they identified the proteins playing a key role in the observed molecular changes.

The results, published in the journal BMC Medicine, highlight the key role of the VEGFA protein, which is linked to blood vessel formation and vascular function, in long COVID. The study shows that this protein is significantly overexpressed in individuals who developed long COVID, particularly in postmenopausal women. "Our findings suggest that vascular dysfunction is a key mechanism in long COVID and that sex and hormonal status may influence its progression", explains Xavier Farré, GCAT-IGTP researcher and first author of the study.

The study, supported by Fundació La Marató de 3CAT, represents an important step in understanding the disease mechanisms and underlines the importance of incorporating sex-stratified approaches into the clinical management of long COVID. Rafael de Cid, scientific director of GCAT and principal investigator of the study at IGTP, states that "the impact of hormonal status on proteins such as VEGFA may be crucial in long COVID and highlights the need to consider these factors both in prognosis and in the development of future treatments. Furthermore, this mechanism could also be relevant to understanding other post-infectious syndromes".

In addition to VEGFA, the study identifies alterations in pathways related to inflammation, chemokine signalling and viral reactivation, and also points to possible muscle damage. These findings open the door to new therapeutic strategies, including treatments aimed at stabilising vascular function.