Vascular-related proteomic signatures in COPD with suspected pulmonary hypertension as predictors of FEV₁ impairment

The development of pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). Despite advances in characterizing pulmonary vascular remodeling in COPD-PH, the lack of targeted therapies limits the routine use of gold-standard invasive diagnostics, highlighting the need for novel biomarkers. The pulmonary vascular endothelium is central to the pathogenesis of both PH and COPD. Since most endothelium-derived modulators of vascular tone and remodeling are targets of endothelial-enriched microRNA-126 (miR-126), a master vascular regulator that is suppressed in COPD, these and related ‘angiocentric molecules’ may be promising biomarkers for COPD-PH. To identify angiocentric proteins elevated in individuals with suspected COPD-PH, defined by a pulmonary artery-to-aorta ratio (PA/A) > 1 on thoracic CT, and to evaluate if they are significantly associated with the severity of airflow limitation (FEV₁). We analyzed plasma proteomic profiles from 1,056 COPDGene Phase-1 participants. Using PA/A > 1 as the outcome, we identified differentially abundant angiocentric proteins. We then assessed the abundance of angiocentric proteins in those with severe airflow obstruction (FEV₁ <50% predicted) among both the COPDGene Phase-1 participants and 188 SPIROMICS Visit-1 participants, and validated the findings in an independent cohort of 363 COPDGene Phase-2 participants. Mediation analyses of multi-omic data examined the relationships between specific miR-126-3p and -p strands levels, their target mRNA and protein levels, and the severity of airflow obstruction. Seventeen angiocentric proteins were increased in participants with PA/A > 1, with interleukin-1 receptor-like 1 (IL1RL1) and platelet-derived growth factor B (PDGFB) showing the most significant elevations. Among those with FEV₁ <50% predicted, eleven angiocentric proteins were increased, including IL1RL1, angiopoietin-2, and peroxiredoxin-5. Mediation analyses supported a contribution of reduced miR-126 levels to lower FEV₁ via select angiocentric molecules, including the direct miR-126 target selenoprotein T. Additionally, LINC01506 and CAPZA1 had a mediation effect on multiple clinical outcomes, including FEV₁, DLCO, and hematocrit. In addition to their role in pulmonary vascular remodeling, miR-126–regulated angiocentric proteins are also linked to airflow limitation, highlighting their potential as candidate biomarkers for COPD-associated pulmonary hypertension.