Specific Aims

Cerebral blood flow impairments are implicated in the pathogenesis of myriad neurological diseases, from concussion 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. While it is accepted that arterioles ensheathed by vascular smooth muscle cells (VSMCs) are capable of regulating perfusion and vasodynamics by modulating vessel diameter, it is debated whether capillaries lined with pericytes can also regulate blood flow. The goal of this dissertation is to define clarify  the elements of the cerebrovasculature that can regulate blood flow under non-pathological conditions.

Pericytes are 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: one study claims that pericytes on capillaries can regulate cerebral blood flow, whereas another 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 differently. These conflicting conclusions and definitions may be explained by ex vivo evidence of cells in the vascular wall that express smooth muscle proteins but have features of pericytes such as protruberant, ovoid cell bodies. Ineed, ex vivo studies from our lab and others have shown that only pericytes near arterioles and venules, but not pericytes in the middle of the capillary bed, are equipped with contractile proteins and other features that are presumably necessary for blood flow regulation. Considering the conflicting in vivo studies, and the heterogeneity of pericytes found ex vivo, I hypothesize that a subset of pericytes can regulate blood flow. I further hypothesize that this subpopulation will possess alpha smooth muscle actin ( (  class="ltx_Math" contenteditable="false" data-equation="\alpha">\(\alpha\)SMA), the primary contractile protein in cerebral blood vessels. 

The entirety of the cerebrovasculature is lined by a pericyte or a  vascular smooth muscle cell (VSMC), conferring these vascular mural cells the perfect positioning for cerebral blood flow control. 

Hypothesis

Pericytes are by definition juxtaposed to the vascular lumen, conferring them perfect positioning for cerebral blood flow control.