Date of Award
2025
Document Type
Campus Access Dissertation
Degree Name
Doctor of Philosophy in Integrative Physiology (PhD)
Administrative Home Department
Department of Kinesiology and Integrative Physiology
Advisor 1
Zhiying Shan
Committee Member 1
Chunxiu Yu
Committee Member 2
Qinghui Chen
Committee Member 3
Xiaoqing Tang
Committee Member 4
Qiuying Sha
Abstract
Hypertension is a leading risk factor for cardiovascular disease worldwide. Among its various contributing factors, unhealthy lifestyle preferences, particularly excessive salt consumption, significantly elevate the risk of hypertension in salt-sensitive individuals. Growing evidence suggests that the brain plays a crucial role in hypertension through overactive endocrine and autonomic responses. Within the brain, the hypothalamic paraventricular nucleus (PVN), an important region in the control of blood pressure (BP), has been recognized as a key driver in hypertension. PVN dysfunction, characterized by inflammation, oxidative stress, enhanced arginine vasopressin (AVP) release, activation of the renin-angiotensin system (RAS), and overactivity of pre-sympathetic neurons, has been implicated in hypertension progression. Recently, extracellular vesicles (EVs), known for mediating intercellular communication by transporting various bioactive cargo, have been linked to hypertension development. However, the role of brain-derived EVs in salt-sensitive hypertension, particularly in relation to PVN dysfunction, remains largely unknown. Study 1 highlighted the acute effects of brain-derived EVs from hypertensive salt-sensitive rats in primary neuronal cultures and brain PVN. Isolated EVs significantly induced neuroinflammation and oxidative stress in the PVN as well as circumventricular organ lamina terminalis. Study 2 explored the long-term effects of central administration of brain-derived EVs from salt-sensitive hypertensive rats on BP regulation. Isolated EVs alone did not increase BP, but sufficient to increase PVN neural activity, enhanced AVP production and induced oxidative stress. Enhanced neural activity and AVP production was also found in the supraoptic nucleus (SON). With combination of high salt, brain-derived EVs from hypertensive rats increased BP, along with elevated water intake and urine output in rats. Study 3 investigated the role of EVs in regulating the RAS within the PVN, with a primary focus on the angiotensin II type 1 receptor (AT1R), a key receptor component of the RAS. Loading small interfering RNA targeting AT1R into brain-derived EVs from hypertensive rats abolished the EV-induced increase in BP and reduced mitochondrial reactive oxygen species (mtROS) accumulation in AT1R+ cells. Collectively, this work uncovered a novel role of brain-derived EVs in salt-sensitive hypertension and highlighted the potential of EV-based drug delivery systems for hypertension treatment.
Recommended Citation
Chen, Xinqian, "EXPLORING THE ROLE OF BRAIN-DERIVED EXTRACELLULAR VESICLES IN SALT-SENSITIVE HYPERTENSION", Campus Access Dissertation, Michigan Technological University, 2025.