Hypoxia-induced angiogenesis is delayed in aging mouse brain

Abstract

Chronic moderate hypoxia results in systemic and central nervous system adaptations that allow acclimatization. Long-term responses to hypoxia involve systemic physiological changes, metabolic regulation, and vascular remodeling. To investigate whether aging affects systemic and cerebral angiogenic adaptational changes in response to prolonged hypoxia, the present study assessed the responses of 4 month old (“young”) C57BL/6 mice and 24 month old (“aged”) C57BL/6 mice to chronic hypobaric hypoxia of 0.4 ATM (290 torr). Compared to young mice, delayed body weight-loss recovery and a lag in polycythemic response were observed in aged mice. As previously shown, Hypoxia Inducible Factor-1α (HIF-1α) accumulation was attenuated and vascular endothelial growth factor (VEGF) expression was decreased in the cerebral cortex of aged mice. Conversely, Cyclooxygenase-2 (COX-2), angiopoietin-2 (Ang-2) and Peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) protein upregulation were not affected in the aged mice. Despite an initial delay in cerebral angiogenic response in aged mice in the first week of hypoxia, no significant differences were observed in microvascular density between young and aged mice in normoxia and at 2 and 3 weeks of hypoxia. Taken together, these observations indicate that even though the HIF-1 response to hypoxia is greatly attenuated, HIF-1 independent compensatory pathways are eventually able to maintain baseline and cerebral angiogenic adaptational changes to chronic hypoxia in aged mice. The delayed adaptive response, however, may result in decreased survival in the aged cohort.

In Vivo Imaging of Cerebral Microvascular Plasticity from Birth to Death

“…While some studies report that metabolic challenges cause vessel formation in the adult brain, 41 our results using time-lapse imaging suggest that the response to hypoxia ceases by 4 months of age. Discrepancies may arise from differences in technical and quantitative approaches.…”

Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats

“…Previous studies demonstrate that advanced aging is associated with a progressive deterioration of microvascular homeostasis due to age-related impairment of angiogenic processes (2,4,66,71,80). It is assumed that these changes have a key role in age-related microvascular rarefaction (79), decreasing tissue blood supply and impairing adaptation to hypoxia (8,41,57). Our present findings extend the results of previous studies (87) showing that aging impairs angiogenic processes in CMVECs, including endothelial cell proliferation, endothelial adhesiveness, and capillary morphogenesis (Figs.…”

Microvascular Structure and Network in the Retina of Patients With Ischemic Stroke

“…Several studies previously have suggested that cerebral small-vessel disease is implicated in ischemic stroke and is considered to be highly related to, but not restricted to, lacunar infarction. 21 Pathological processes in the brain such as atherosclerosis, lipohyalinosis, and arteriosclerosis lead to the destruction and occlusion of small perforating vessels 21,22 and cause vessel wall remodeling, resulting in elongated and tortuous vessels associated with increased vascular leakage. 21 These changes affect the ability of cerebral arterioles to maintain control of local blood flow, predisposing areas served by these dysfunctional vessels to ischemic damage.…”