# Specific Aims

## Goals of the proposed research

Cerebral blood flow impairments are implicated in the pathogenesis of myriad neurological diseases, from multiple sclerosis to dementia. Understanding how cerebral blood flow is regulated under normal conditions may thus permit the development of therapies that can correct blood flow abnormalities and thereby alter the trajectory of neurological diseases. Studies consistently reveal two broad categories of blood flow impairment: 1. abnormal perfusion (hypo- or hyperperfusion), and 2. dampened vasodynamics, defined as a reduced ability of the cerebrovasculature to rapidly change resistance to blood flow in response to environmental shifts such as neural activity, blood pressure, oxygen level, etc. The cells responsible for regulating perfusion and vasodynamics are vascular mural cells, comprised of vascular smooth muscle cells (VSMCs) and pericytes, which adorn the abluminal endothelium. While it is accepted that arterioles ensheathed by vascular smooth muscle cells (VSMCs) are capable of regulating blood flow by modulating vessel diameter, it is debated whether capillaries lined with pericytes can also regulate blood flow. The goal of this dissertation is to clarify the elements of the cerebrovasculature that can regulate blood flow under non-pathological conditions.

## Hypothesis

Pericytes are by definition embedded in the capillary basement membrane, placing them in a perfect position to control capillary blood flow. However, in vivo investigations into the capacity of pericytes to regulate capillary blood flow provide opposing conclusions, placing the field in a stalemate. Hall, et al. (2014) claim that pericytes on capillaries can regulate cerebral blood flow, whereas Hill, et al. (2015) concluded that VSMCs on arterioles can control blood flow, but pericytes on capillaries cannot. Adding to the uncertainty of which cerebrovascular elements regulate blood flow in vivo, these studies defined pericytes and capillaries differently. Hall, et al. (2014) categorized all branches coming from a penetrating arteriole as a capillary, and any vascular mural cell on these branches as a pericyte. Meanwhile, Hill, et al. (2015) identified pericytes and capillaries by the absence of alpha smooth muscle actin (﻿﻿﻿﻿$$\alpha$$SMA), a protein that confers contractile ability to VSMCs. To advance the field beyond this stalemate, we aim to identify which regi