Endothelial and Angiogenic Biomarkers in Obstructive Sleep Apnea: Longitudinal Associations With Continuous Positive Airway Pressure
Lead. Does continuous positive airway pressure (CPAP) therapy meaningfully alter the vascular biology that drives cardiovascular risk in obstructive sleep apnea (OSA)? A new prospective cohort study published in Archivos de Bronconeumología provides the longest longitudinal data to date, tracking endothelial and angiogenic biomarkers over five years in patients with moderate-to-severe OSA treated with CPAP. The results suggest CPAP attenuates one key pathway (hypoxia-driven VEGF signaling) while leaving another (Angiopoietin-2) largely unaffected, pointing to distinct and potentially independent mechanisms of vascular injury in sleep apnea.
What they found
Led by David Sanz-Rubio and colleagues from CIBER, IIS-Aragón, Hospital Universitario Miguel Servet, and other Spanish institutions, the study enrolled 326 participants from the EPIOSA cohort, including 195 adults with moderate-to-severe OSA who received CPAP (mean usage 6.7 hours per night) and 72 non-OSA controls. Researchers measured four circulating biomarkers at baseline, one year, and five years: vascular endothelial growth factor (VEGF), Angiopoietin-2 (Ang-2), Tie-2, and E-selectin.
The findings diverged sharply by biomarker.
VEGF, a signaling protein that promotes blood vessel growth in response to hypoxia, showed sustained reductions at both the one-year and five-year follow-ups among CPAP-treated patients. The decrease was independently associated with baseline VEGF levels and waist-to-hip ratio, a marker of central obesity. This pattern is consistent with the hypothesis that CPAP reduces intermittent hypoxia, thereby dialing down the VEGF signal.
Ang-2, a regulator of vascular permeability and inflammation, moved in the opposite direction. Levels increased over time in both the OSA and control groups, with no association to CPAP pressure settings or hours of nightly use. Baseline Ang-2 was independently predicted by body weight and soluble ST2 (sST2), a marker of cardiac stress and fibrosis. The upward trajectory appeared unrelated to CPAP therapy, suggesting factors beyond hypoxia drive this biomarker.
Tie-2 and E-selectin showed minimal temporal variation across all groups over the five-year window.
Why it matters
Cardiovascular disease remains the leading cause of morbidity and mortality in OSA, but the biological pathways linking intermittent hypoxia to vascular damage are not fully understood. This study contributes evidence that CPAP may selectively modify some but not all of those pathways.
The sustained VEGF reduction is clinically encouraging. VEGF is a downstream effector of hypoxia-inducible factor 1 (HIF-1), and its attenuation signals that the therapy is reaching the hypoxic trigger. If confirmed in larger trials, VEGF could serve as a longitudinal biomarker of CPAP efficacy at the molecular level, complementing standard measures such as the apnea-hypopnea index and oxygen desaturation metrics.
The Ang-2 finding is arguably more provocative. If CPAP does not alter Ang-2 trajectories, and if Ang-2 is independently linked to body weight and sST2, then non-hypoxic mechanisms (possibly including systemic inflammation, mechanical stretch from obesity, or subclinical cardiac remodeling) may sustain vascular risk even in patients who use CPAP consistently. This raises the possibility that adjunctive therapies targeting inflammation or metabolic health may be needed alongside airway pressure to fully address cardiovascular risk in OSA.
Limits
The study is observational, not a randomized controlled trial, so causal inferences about CPAP’s effect on biomarker trajectories are constrained. The control group comprised individuals without OSA rather than a placebo-CPAP or untreated-OSA group, which limits the ability to separate the natural history of the biomarkers from the effect of therapy. All participants were free of cardiovascular comorbidities at enrollment, so results may not generalize to OSA patients with established heart disease. Biomarker measurements were limited to four analytes; a broader proteomic or transcriptomic panel could reveal additional pathways. CPAP adherence, while reasonably high on average, was measured by device downloads and may not capture day-to-day variability in effective pressure delivery.
Bottom line
In otherwise healthy patients with moderate-to-severe OSA, long-term CPAP is associated with attenuation of hypoxia-driven VEGF pathways without altering Ang-2 trajectories. The differential behavior of these two biomarkers supports the view that vascular risk in OSA is mediated through at least two distinct mechanisms, only one of which is hypoxia-dependent and CPAP-responsive. Further research should investigate whether combining CPAP with interventions targeting inflammation, adiposity, or cardiac remodeling yields additive vascular benefits.
Source
Sanz-Rubio D, Cubillos-Zapata C, Marin-Oto M, Diaz-Garcia E, Rodriguez-Sanz J, Perez-Moreno P, Lopez-Fernandez C, Garcia-Rio F, Marin JM. Endothelial and Angiogenic Biomarkers in Obstructive Sleep Apnea: Longitudinal Associations With Continuous Positive Airway Pressure. Arch Bronconeumol. 2026. doi:10.1016/j.arbres.2026.06.005
PMID: 42373343
id: 42373343
pmid: 42373343
url: https://pubmed.ncbi.nlm.nih.gov/42373343/