Date of Award

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Marilyn M. Cipolla

Abstract

Stroke is the second leading cause of death worldwide and the leading cause of devastating disability. Leptomeningeal anastomoses (LMAs) are small distal anastomotic vessels, also known as pial collaterals in the brain. These vessels redirect blood flow during an occlusion and are important for stroke treatment and outcome. Hypertension, a major risk factor for stroke, is associated with limited amounts of salvageable tissue, greater perfusion deficit and worse stroke outcome. Angiotensin II (Ang II), generated from angiotensin I by angiotensin converting enzyme (ACE), is importantly involved in the pathogenesis of hypertension. Despite the important clinical implications, functions of LMAs in physiological and hypertensive conditions remain largely unknown. Thus, the overall goal of this dissertation was to determine the functional properties of LMAs in physiological condition, and the detrimental effects of hypertension on LMA function.We first describe our findings determining the effect of 2, 3, 5-triphenyltetrazolium chloride (TTC) treatment on immunohistochemical quantification of rat brains after ischemic stroke. TTC is a vital dye that is commonly used to measure infarct volume in stroke preclinical therapeutic studies. Here, we compared the collagen IV immunohistochemical staining intensity between TTC-treated and non-TTC-treated rat brain sections. We found that TTC treatment caused a significantly lower autofluorescence, but it did not affect collagen IV staining intensity compared with controls. Thus, these results indicate that TTC-treated brain sections are viable for immunohistochemical quantification. Next, we present our investigations on the structural and functional differences in primary and pial collateral circulations in adult normotensive male and female rats. We compared the function and structure of LMAs and found no sex difference. We also confirmed no sex difference in primary and pial collateral flow during ischemic stroke in normotensive rats. These findings suggest that the reduced severity of stroke outcome in female rats is not likely due to the cerebral collateral circulation. Then, we studied the underlying mechanisms by which hypertension causes LMA vasoconstriction. Our results demonstrated that LMAs from hypertensive rats had considerable myogenic tone and impaired vasodilatory responses that were Ang II-dependent. Importantly, only ACE inhibitor treatment, not the Ang II-independent antihypertensive agent hydralazine, completely reversed the increased vasoconstriction and impaired vasodilation. These findings indicate that ACE inhibition may be beneficial to collateral flow when stroke occurs in the setting of chronic hypertension, thus should be considered as a preferable antihypertensive treatment than hydralazine. Finally, we present our research findings on mechanisms of flow-mediated vasodilation of LMAs in physiological and hypertensive conditions. We found that LMAs from normotensive rats dilated to increased flow and shear stress, and this response was mediated by endothelium-dependent vasodilation. However, the vasodilation was significantly impaired in hypertensive rats, where it was Ang II-dependent. These results demonstrate flow and shear stress-induced vasodilation in LMAs from normotensive rats, suggest the mechanisms of how pial collaterals are poorly engaged during ischemic stroke in chronic hypertension. In summary, this dissertation describes the function of LMAs in physiological condition, and mechanisms by which chronic hypertension causes impaired LMA function.

Language

en

Number of Pages

296 p.

Available for download on Wednesday, August 09, 2023

Included in

Pharmacology Commons

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