VEGFA Sex-Specific Signature is associated to long COVID Symptom Persistence, 2025, Farré et al

[Nightsong]

Now published, see next post.
--------------------------------------------

Abstract:
Background. Long COVID involves persistent symptoms after COVID-19 recovery, affecting multiple organ systems for months or years. Risk factors include female sex, prior chronic conditions, severe SARS-CoV-2 infection, reinfections, and lack of vaccination. As a major public health concern, ongoing research continues to investigate its causes, mechanisms, and long-term effects.

Methods. Proteomic expression analysis of 171 individuals, in two time points, with confirmed SARS-CoV-2 infection, including 133 long COVID patients from the deeply characterized COVICAT cohort, assessed 1,395 protein biomarkers using Olink® technology. Statistical analyses with linear mixed models examined protein expression changes, long COVID status, and sex-specific differences. Functional analysis included Gene Set Enrichment Analysis (GSEA) and protein–protein interaction (PPI) networks.

Findings. Findings revealed dysregulated chemokine signaling, complement activation, and viral reactivation, aligning with prior studies, and identified VEGFA overexpression in long COVID patients (effect size 0.322, SE = 0.098, p = 0.0013), along with sex-specific expression patterns. Network analysis detected 109 nodes and 274 edges, with VEGFA ranking highest across all centrality metrics.

Interpretation. By integrating comprehensive proteomic data from a well-characterized cohort, we identified sexually dimorphic patterns in protein expression in long COVID patients. Sex-based differences in protein dynamics suggest distinct immune and vascular recovery trajectories. VEGFA's role in ovarian function, cyclical expression, and uterine involvement may explain sex differences in long COVID susceptibility.

Link | PDF (SSRN preprint, May 2025, open access)

 

[SNT Gatchaman]

Now published —

VEGFA sex-specific signature is associated to long COVID symptom persistence

Spoiler: Authors

Farré, Xavier; Blay, Natalia; Iraola-Guzmán, Susana; Fernández-Jiménez, Francisco; Alzate-Piñol, Sayoa; Llucià-Carol, Laia; Espinosa, Ana; Castaño-Vinyals, Gemma; Dobaño, Carlota; Moncunill, Gemma; Karachaliou, Marianna; Garcia-Aymerich, Judith; Kogevinas, Manolis; Barceló, Carles; Cadenas, Israel; de Cid, Rafael

BACKGROUND
Long COVID involves persistent symptoms after COVID-19 recovery, affecting multiple organ systems for months or years. Risk factors include female sex, prior chronic conditions, severe SARS-CoV-2 infection, reinfections, and lack of vaccination. As a major public health concern, ongoing research continues to investigate its causes, mechanisms, and long-term effects.

METHODS
Proteomic expression analysis of 171 individuals, in two time points, with confirmed SARS-CoV-2 infection, including 133 long COVID patients from the deeply characterized COVICAT cohort, assessed 1395 protein biomarkers using Olink® technology. Statistical analyses with linear mixed models examined protein expression changes, long COVID status, and sex-specific differences. Functional analysis included gene set enrichment analysis and protein–protein interaction networks.

RESULTS
Findings revealed VEGFA overexpression in long COVID patients (effect size 0.322, SE = 0.098, p = 0.0013), along with sex-specific expression patterns and the influence of sex-hormonal status in females, with significant overexpression of circulating VEGFA levels specifically in postmenopausal women (Mann–Whitney U test p value = 8.55 × 10−3). Network analysis identified 109 nodes and 274 edges, with VEGFA ranking highest in centrality. Dysregulated chemokine signaling, complement activation, and viral reactivation were also confirmed, consistent with prior studies.

CONCLUSIONS
Using high-throughput proteomic profiling in a population-based cohort, we observed that vascular dysfunction, particularly involving VEGFA, is a key feature of long COVID, especially in milder cases, with significant overexpression of VEGFA in postmenopausal women. Sex-specific proteomic patterns suggest distinct recovery mechanisms, highlighting the need to consider sex, vascular health, and disease severity in the pathogenesis and management of long COVID.

Web | PDF | BMC Medicine | Open Access

 

[Dolphin]

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

Un estudi liderat per GCAT-IGTP relaciona la proteïna VEGFA amb la COVID persistent, especialment en dones postmenopàusiques, i apunta a un mecanisme vascular com a causa dels símptomes. Els resultats subratllen la importància de tenir en compte el sexe i l'estat hormonal en la recerca i el...

www.eurekalert.org

News Release 13-Oct-2025

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

Peer-Reviewed Publication
Germans Trias i Pujol Research Institute



image:

Rafael de Cid and Xavier Farré, authors of the study from the GCAT|Genomes for Life team at IGTP

view more


Credit: IGTP

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.

---

Journal​

BMC Medicine

DOI​

10.1186/s12916-025-04402-6

Method of Research​

Data/statistical analysis

Subject of Research​

Human tissue samples

Article Title​

VEGFA sex-specific signature is associated to long COVID symptom persistence

Article Publication Date​

10-Oct-2025

COI Statement​

The authors declare no competing interests.