Aging Exacerbates Pressure-Induced Mitochondrial Oxidative Stress in Mouse Cerebral Arteries: Figure 1.

Abstract

Epidemiological studies demonstrate that in addition to the increased prevalence of hypertension in old patients, the deleterious cerebrovascular effects of hypertension (including atherosclerosis, stroke, and vascular cognitive impairment) are also exacerbated in elderly individuals. The cellular mechanisms by which aging and hypertension interact to promote cerebrovascular pathologies are not well understood. To test the hypothesis that aging exacerbates high pressure-induced mitochondrial oxidative stress, we exposed isolated segments of the middle cerebral arteries of young (3 months) and aged (24 months) C57BL/6 mice to 60 or 140 mmHg intraluminal pressure and assessed changes in mitochondrial reactive oxygen species production using a mitochondria-targeted redox-sensitive fluorescent indicator dye (MitoSox) by confocal microscopy. Perinuclear MitoSox fluorescence was significantly stronger in high pressure-exposed middle cerebral arteries compared with middle cerebral arteries of the same animals exposed to 60 mmHg, indicating that high pressure increases mitochondrial reactive oxygen species production in the smooth muscle cells of cerebral arteries. Comparison of young and aged middle cerebral arteries showed that aging exacerbates high pressure-induced mitochondrial reactive oxygen species production in cerebral arteries. We propose that increased mechanosensitive mitochondrial oxidative stress may potentially exacerbate cerebrovascular injury and vascular inflammation in aging.

Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype

“…Results of previous experimental studies by our laboratories (Toth et al ., 2015b), and by others (Wakisaka et al ., 2010a,b), identify oxidative stress as a critical factor contributing to hypertension‐induced MMP activation and pathogenesis of CMHs and demonstrate that high intraluminal pressure per se (via increased wall tension‐dependent cellular stretch) is a key stimulus for increased vascular production of ROS (Ungvari et al ., 2003; Springo et al ., 2015; Toth et al ., 2015b) that lead to MMP activation. To elucidate the likely mechanism contributing to the exacerbation of hypertension‐induced MMP activation in IGF‐1 deficiency, we compared pressure‐induced production of ${\mathrm{O}}_2^{·-}$ in cerebral arteries isolated from IGF‐1‐deficient mice and their respective age‐matched controls using the redox‐sensitive dye dihydroethidium (DHE).…”

“…This concept is supported by recent findings showing that age‐related exacerbation of hypertension‐induced MMP activation can be abolished by antioxidative treatments (Toth et al ., 2015b). Increased hypertension‐induced oxidative stress in aged arteries has been attributed to upregulation of NOX oxidases, increased mitochondrial ROS generation, and impaired Nrf2‐dependent antioxidant defense mechanisms (Ungvari et al ., 2011a,b; Springo et al ., 2015; Toth et al ., 2015b). There is evidence that inhibition of ROS synthesis by these sources can prevent development of CMHs in aging (Toth et al ., 2015b).…”

“…In separate experiments, pressure‐induced ROS production was measured in cannulated segments of the middle cerebral arteries, as described (Springo et al ., 2015; Toth et al ., 2015b). In brief, the arteries from each control and IGF‐1‐deficient mice were pressurized to 60 or 160 mmHg for 4 h. To characterize high‐pressure‐induced vascular ROS production, at the end of the incubation period, the vessels were loaded with the redox‐sensitive dye DHE (Invitrogen, Carlsbad, CA, USA; 3 × 10 −6  mol L −1 ; for 30 min).…”

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

“…Moreover, Pung et al have shown that chronic inhibition of Complex I by rotenone blocks ischemia induced collateral artery growth in the coronary circulation via activation of adenosine monophosphate-activated kinase and the subsequent inhibition of mechanistic target of rapamycin (mTOR) and p70 ribosomal S6 kinase (126). Higher levels of cellular ROS, such as occurs during injury and disease, can lead to cell death via both mitochondrial-and nonmitochondrial-mediated pathways, especially in metabolically compromised conditions (6,23,29,38,93,138).…”

“…Although production of ROS by mitochondria appears to be an independent process under most conditions, recent reports indicate that ROS production by mitochondria can promote ROS production by the extramitochondrial NADPH oxidase system, or vice versa, via a positive feedback system (23,31,37,134,138). Thus, the interaction between the mitochondria and the cytosolic NADPH oxidase axis leads to cellular damage due to excessive production of ROS by a "ROS induced ROS" mechanism.…”