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

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.

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.

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.

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.