How a Single Protein Reveals Sex-Specific Secrets of Long COVID
The discovery of a single protein's behavior is rewriting the story of Long COVID and pointing to why women's bodies tell a different tale.
When COVID-19 survivors began reporting lingering symptoms weeks and months after their initial infection, the medical community faced a new mystery. This condition, known as Long COVID, presented with a confusing array of symptoms across virtually every organ system. Even more puzzling was a consistent pattern: women were disproportionately affected. Recent groundbreaking research has uncovered a crucial piece of this puzzle—a protein called VEGFA that behaves differently in men and women with Long COVID, offering new insights into why biology matters in recovery.
Long COVID, medically known as post-acute sequelae of SARS-CoV-2 infection, refers to the persistence of symptoms long after the acute phase of COVID-19 has passed. According to the World Health Organization, these symptoms typically emerge within three months of infection and last for at least two months, often much longer.
The condition has become a major public health concern, with an estimated 10% of infected individuals experiencing persistent symptoms 7 .
Epidemiological studies have consistently identified female sex as a significant risk factor for developing Long COVID. A comprehensive analysis from the RECOVER study involving over 12,000 participants found that women had a 31% higher risk of developing Long COVID compared to men, even after accounting for other risk factors . The risk was particularly pronounced for women between 40 and 54 years old, where the risk increased to 45% higher than men of the same age .
31%
Higher risk for women overall
45%
Higher risk for women 40-54 years
42%
Higher risk for postmenopausal women
A 2024 systematic review of 6,849 patients found women had significantly higher risk of various neurological symptoms compared to men 8 :
Initially considered primarily a respiratory illness, COVID-19 is now recognized as a disease that can affect the vascular system—the network of blood vessels that circulates blood throughout the body. The endothelium, a single layer of cells lining our blood vessels, appears to be particularly vulnerable to SARS-CoV-2 infection.
When the endothelium becomes damaged or dysfunctional, it can lead to a cascade of problems, including increased inflammation, abnormal blood clotting, and disrupted blood flow to vital organs 7 .
This vascular dysfunction may explain why Long COVID can affect so many different organ systems simultaneously.
Enter Vascular Endothelial Growth Factor A (VEGFA), a protein that plays a critical role in maintaining and forming blood vessels. Under normal conditions, VEGFA helps regulate vascular permeability and promotes healing. But in the context of Long COVID, this essential protein appears to be dysregulated in ways that differ strikingly between men and women.
VEGFA - Central node in protein interaction network
109 nodes and 274 edges in VEGFA interaction network 1
In 2025, a landmark study published in BMC Medicine revealed startling findings about VEGFA's role in Long COVID 1 5 . Researchers conducted a sophisticated proteomic analysis of 171 individuals from the COVICAT cohort, measuring 1,395 different protein biomarkers at multiple time points.
The study included 133 Long COVID patients and 38 recovered controls, all with confirmed SARS-CoV-2 infection 1 . Participants were drawn from the deeply characterized COVICAT cohort in Catalonia, with data linked to electronic health records 1 .
Using advanced Olink® technology, researchers analyzed blood samples to measure protein concentrations with high precision 1 5 .
The team used linear mixed models to examine protein expression changes, accounting for Long COVID status, sex differences, and hormonal status in women 1 .
Beyond individual proteins, researchers mapped protein-protein interaction networks to understand how VEGFA connects to other molecular players 1 .
| Characteristic | Long COVID Group | Recovered Control Group |
|---|---|---|
| Number of Participants | 133 | 38 |
| Sex Distribution | Reflected population risk (higher female) | Reflected population recovery |
| Sample Collection | Two time points (2020 & 2023) | Two time points (2020 & 2023) |
| Symptom Assessment | Self-reported using WHO definition | Asymptomatic at follow-up |
| Data Linkage | Electronic health records | Electronic health records |
The findings were striking. Researchers discovered significant VEGFA overexpression in Long COVID patients compared to recovered individuals, with an effect size of 0.322 and a highly significant p-value of 0.0013 1 5 .
Even more intriguing was the sex-specific pattern: postmenopausal women showed particularly significant overexpression of circulating VEGFA levels (Mann-Whitney U test p-value = 8.55 × 10−3) 1 5 .
Effect size: 0.322
Standard Error: 0.098
p-value: 0.0013
Mann-Whitney U test
p-value: 8.55 × 10−3
| Finding | Statistical Significance | Biological Interpretation |
|---|---|---|
| VEGFA overexpression in Long COVID | Effect size 0.322, SE = 0.098, p = 0.0013 | Vascular dysfunction is a key feature of Long COVID |
| Specific elevation in postmenopausal women | Mann-Whitney U test p = 8.55 × 10−3 | Hormonal status influences VEGFA regulation |
| Network centrality | Highest ranking in protein interaction network | VEGFA may coordinate multiple pathological processes |
The discovery that VEGFA dysregulation is particularly pronounced in postmenopausal women points to the significant role of sex hormones in Long COVID. Estrogen is known to influence both immune function and vascular health, and the decline of estrogen during menopause may create conditions where VEGFA becomes more dysregulated after SARS-CoV-2 infection 1 .
45%
Higher risk for women 40-54 years
42%
Higher risk for postmenopausal women
0%
Baseline risk for men
The RECOVER study noted that menopause slightly decreased this risk, but postmenopausal women still maintained a 42% higher risk than men .
The relationship between menopausal status and Long COVID risk suggests that hormonal changes create a window of vulnerability, possibly through effects on both the immune system and vascular function.
Estrogen influences immune function and vascular health. The decline during menopause may disrupt normal VEGFA regulation.
Hormonal changes affect the interface between the immune system and vascular function, creating vulnerability to Long COVID.
Modern biomedical research relies on sophisticated tools to unravel complex biological puzzles. The VEGFA discovery was made possible by several key technologies:
| Tool/Technology | Function in Research |
|---|---|
| Olink® Proteomics | High-throughput protein measurement allowing simultaneous analysis of 1,395 biomarkers 1 |
| Linear Mixed Models | Statistical method that accounts for multiple variables and repeated measurements over time 1 |
| Protein-Protein Interaction Networks | Mapping technique visualizing how proteins interact within biological systems 1 |
| Electronic Health Record Linkage | Connects laboratory findings with clinical outcomes and patient characteristics 1 |
While VEGFA represents a crucial finding, it's not the only immune factor showing sex-specific patterns in Long COVID. A 2024 study published in Science Translational Medicine identified several other sex-specific immune pathways 2 .
Males who developed Long COVID showed increases in transforming growth factor-β (TGF-β) signaling during acute infection 2 .
Females demonstrated reduced TGFB1 expression and had increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared to females who recovered 2 .
The study also found common immune features across sexes, including alterations in monocyte phenotype and activation state, suggesting that while some mechanisms differ by sex, others are shared 2 .
The discovery of VEGFA's sex-specific signature in Long COVID has significant implications for future treatments. Rather than a one-size-fits-all approach, these findings suggest that effective interventions may need to be tailored to a patient's sex and hormonal status.
The RECOVER study emphasizes that "better understanding of sex-specific Long COVID risk can help identify which patients may develop Long COVID, develop potential treatments that are tailored for specific populations, and improve care for people living with Long COVID" .
The discovery of VEGFA's sex-specific signature in Long COVID represents more than just a scientific curiosity—it highlights the essential importance of considering sex as a biological variable in medical research. For too long, women's health has been understudied, leading to gaps in our understanding of how diseases manifest differently across sexes.
As research continues to unravel the complex interplay between viruses, vascular health, and our immune systems, one thing becomes increasingly clear: solving the Long COVID mystery requires us to look at the whole picture—and that picture looks different in men and women.
The road to effective Long COVID treatments will likely be paved with personalized approaches that account for our biological individuality. The VEGFA story reminds us that sometimes, the most important answers lie not in what we have in common, but in what makes us different.