Despite a long-standing recognition of the importance of spontaneous intracranial hemorrhage (ICH) during hypertension, our understanding of the pathogenesis of ICH remains incomplete. Alterations in cerebrovascular structure that accompany hypertension, such as inward remodeling (defined as rearrangement of vascular components around a smaller lumen) and hypertrophy, reduce stress in the vessel wall, and thus have the potential to protect against spontaneous ICH in hypertension. The investigators have obtained preliminary data in mice that suggests whereas hypertrophy of cerebral arterioles may indeed protect against ICH, inward remodeling does not protect, and may promote ICH. Mechanisms that contribute to inward remodeling and hypertrophy may play especially important roles in promoting, or protecting against, ICH. The major goal of studies that are now proposed is to examine mechanisms of inward remodeling in cerebral arterioles in relation to mechanisms of spontaneous ICH. A combination of established in vivo, histological, immunohistochemical and biochemical methods combined with genetically altered mice, pharmacological inhibitors, and a novel model of spontaneous ICH will be used to test the central hypothesis of this proposal that biochemical pathways that lead to inward remodeling and hypertrophy play different roles in modulating susceptibility to ICH with activation of JNK and MMPs contributing to inward remodeling, but not hypertrophy, and predisposing to ICH; and EGF-R contributing to hypertrophy, but not inward remodeling, and protecting against ICH. The following specific aims will be examined.
The first aim i s to test the hypothesis that activation of c-jun N-terminal kinase (JNK) and matrix metalloproteinase (MMP) are important in inward remodeling. The roles of JNK and MMPs in inward remodeling of cerebral arterioles will be examined using angiotensin (Ang) II infusion to induce hypertension in JNK1 deficient mice and MMP9 deficient mice, and in C57BL/6J mice treated with inhibitors of JNK and MMPs. Oxidative stress and MMPs will be evaluated with dihydroethidine and in situ zymography, respectively.
The second aim i s to test the hypothesis that activation of JNK and MMPs, together with inward remodeling, do not protect against hypertensive ICH, and may even contribute to it, whereas transactivation of EGF-R and cerebral arteriolar hypertrophy protect against ICH. Studies planned in this aim will use a model of ICH developed by the investigators that is easily applied in genetically altered mice to determine whether prevention of inward remodeling by genetic deficiency or inhibition of JNK and MMPs reduces susceptibility to ICH, and whether prevention of cerebral arteriolar hypertrophy by inhibition of epithelial growth factor receptor increases susceptibility to ICH. These studies may provide important insight into mechanisms that produce, and protect against, spontaneous ICH in hypertension, and thus may lead to novel approaches to prevent and treat ICH.
Structural changes in blood vessels in the brain have emerged as a potentially major risk factor in several diseases associated with hypertension in humans, including hemorrhagic stroke and Alzheimer's disease. The goal of the studies proposed in this application is to increase our understanding of factors that contribute to structural changes that occur in blood vessels in the brain during hypertension, such as oxidative stress and factors that regulate activity in vascular cells. Achieving this goal, therefore, may provide important new insights, which, together with other advances in this area, may translate into strategies for reducing complications associated with hypertension.
