Aging exacerbates hypertension‐induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection

Abstract

Recent studies demonstrate that aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension-induced CMHs young (3 months) and aged (24 months) mice were treated with angiotensin II plus L-NAME. We found that the same level of hypertension leads to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Hypertension-induced cerebrovascular oxidative stress and redox-sensitive activation of matrix metalloproteinases (MMPs) were increased in aging. Treatment of aged mice with resveratrol significantly attenuated hypertension-induced oxidative stress, inhibited vascular MMP activation, significantly delayed the onset, and reduced the incidence of CMHs. Collectively, aging promotes CMHs in mice likely by exacerbating hypertension-induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high-risk elderly patients.

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).…”

“…We found that gait abnormalities (including a significant decline in regularity index, speed, and stride length; Fig. 2A–C, respectively) were significantly more severe in hypertensive IGF‐1‐deficient mice as compared to hypertensive control mice, suggesting that analysis of motor function status (e.g., deficit in interlimb coordination, temporal asymmetry) can predict the severity of CMH burden (Toth et al ., 2015b). Hypertension‐induced changes in base of support did not correlate with IGF‐1 status (Fig.…”

“…Hypertension‐induced activation of MMPs is thought to play a central role in the pathogenesis of CMHs (Wakisaka et al ., 2010a,b; Toth et al ., 2015b). To determine how interaction of IGF‐1 deficiency and hypertension affect vascular MMP activity, MMPsense 645 FAST substrate was administered in vivo and vascular MMP activation was compared between hypertensive IGF‐1‐deficient mice and hypertensive age‐matched controls by measuring MMPsense fluorescence in brain homogenates.…”

“…Other studies reached the same conclusion, reporting 56% prevalence for CMHs in elderly hypertensive subjects (Kato et al ., 2002). Recent data from animal models extend the clinical findings, demonstrating that aging and hypertension synergistically interact to exacerbate the development of CMHs (Toth et al ., 2015b). Our current understanding, based on experimental data, is that aging promotes the development of CMHs by exacerbating hypertension‐induced oxidative stress and redox‐sensitive activation of matrix metalloproteases (MMPs) compromising the structural integrity of the cerebral microvasculature (Toth et al ., 2015b).…”

“…Recent data from animal models extend the clinical findings, demonstrating that aging and hypertension synergistically interact to exacerbate the development of CMHs (Toth et al ., 2015b). Our current understanding, based on experimental data, is that aging promotes the development of CMHs by exacerbating hypertension‐induced oxidative stress and redox‐sensitive activation of matrix metalloproteases (MMPs) compromising the structural integrity of the cerebral microvasculature (Toth et al ., 2015b). Yet, the specific age‐related mechanism(s) that underlie the increased susceptibility of the aged cerebral vasculature to rupture remain elusive.…”