Temporal Coordination of Angiogenic, Nitric Oxide, and Endothelin Pathways in Vascular Adaptation to Hypoxia and Reoxygenation.

PURPOSE: Hypoxia induces dynamic vascular adaptations that evolve over time and are further modified by reoxygenation. Although vascular responses are commonly described as either adaptive or maladaptive, the temporal progression of key endothelial signaling pathways remains incompletely integrated across the literature. This narrative review examines how vascular endothelial growth factor (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), nitric oxide synthase trafficking inducer (NOSTRIN), endothelin-1 (ET-1), and angiopoietin/Tie2 signaling contribute to vascular adaptation and dysfunction during acute, subacute, chronic hypoxia, and reoxygenation.

METHODS

A narrative review of experimental and clinical literature was performed using PubMed/MEDLINE, Embase, Scopus, and Web of Science. Studies evaluating temporal hypoxia-related vascular responses, endothelial signaling pathways, angiogenesis, vascular remodeling, and reperfusion-related mechanisms were synthesized to develop an integrated mechanistic framework.

RESULTS

Acute hypoxia activates compensatory vascular responses characterized by VEGF induction, endothelial adaptation, and modulation of vasodilatory signaling. During subacute hypoxia, angiogenic and remodeling pathways become increasingly engaged, accompanied by progressive endothelial destabilization. Prolonged hypoxia promotes persistent VEGF signaling but is associated with increased anti-angiogenic influences, impaired NO bioavailability, enhanced ET-1 activity, Ang-2 predominance, endothelial dysfunction, and maladaptive vascular remodeling. Reoxygenation represents a distinct biological state in which oxidative stress, inflammation, and endothelial injury may either impair recovery or facilitate restoration of vascular homeostasis, depending on the balance between reparative and damaging pathways.

CONCLUSION

Vascular adaptation to hypoxia is fundamentally time-dependent and regulated by interconnected endothelial signaling networks. Integrating temporal changes in VEGF/sFlt-1, eNOS/NO, ET-1, NOSTRIN, and Ang/Tie2 pathways provides a mechanistic framework for understanding the transition from adaptive vascular responses to chronic vascular dysfunction and for identifying potential therapeutic targets.