Fellowship for Dominic Nthenge: Pre-Existing Hypertension Amplifies Cerebrovascular Pathology After Brain Injury: Role of Central AT1Rs

Abstract Traumatic brain injury (TBI) can result in death or substantial disability, imposing significant socio-economic burdens on survivors. While the extent of brain damage and behavioral deficits accompanying TBI depend on type and severity of insult, they may also be modulated by age, sex, and comorbidities such as psychiatric issues, substance abuse, diabetes or hypertension. Indeed, as nearly half of all US adults suffer from hypertension, it is one of the most common premorbid conditions in people that experience a moderate to severe TBI. Hypertension has been linked to cerebrovascular damage, neuroinflammation, and cognitive decline. In cases where hypertension is unresponsive to traditional anti-hypertensive medications, initiation and maintenance of elevated blood pressure is believed to be controlled by the local renin angiotensin system within the brain. Despite an overlap in several aspects of brain pathology induced by hypertension and triggered by TBI, little is understood about the impact of premorbid hypertension on outcomes following TBI. We hypothesize that pre-existing hypertension creates enhanced vulnerability to TBI, resulting in greater cerebrovascular damage and neuroinflammation and that these effects are mediated through central angiotensin type 1 receptor (AT1R) activation. To test this hypothesis, we will pursue two aims. In the first aim, a moderate TBI or sham injury will be delivered to normotensive mice and mice with 3 weeks of pre-injury hypertension, generated by continuous subcutaneous infusion of angiotensin-II (Ang-II). Several metrics of brain damage including blood-brain barrier dysfunction, impaired neurovascular coupling and neuroinflammation will be compared in hypertensive and normotensive mice at 1 week after injury. In the second aim, brain AT1Rs will be blocked using intranasal administration of Losartan, a well-known AT1R antagonist, during the three-week hypertension period preceding TBI. This aim will identify whether additive effects of premorbid hypertension on TBI-induced brain damage and motor and cognitive impairment are abrogated by central inhibition of AT1Rs. These findings will provide novel data implicating pre-morbid hypertension as a significant modifier of TBI outcomes, necessitating greater inclusion and consideration of this risk factor in preclinical and clinical studies. In addition, implicating brain AT1Rs in hypertension- related risk in CNS injury will open new avenues for mechanistic inquiry.