Specific Aims

Cerebral blood flow impairments are implicated in the pathogenesis of myriad neurological diseases, from multiple sclerosis to subarachnoid hemorrhage. 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 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, placing the field in a stalemate: 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 in vivo studies defined pericytes differently. One study identified pericytes by the appearance of a protruberant ovoid cell body, a hallmark of pericytes, whereas the other study identified pericytes by the lack of alpha smooth muscle actin ( (  class="ltx_Math" contenteditable="false" data-equation="\alpha">\(\alpha\)SMA), a protein that is known to confer contractile ability to VSMCs. These conflicting conclusions and definitions may be reconciled by findings from our lab and others that show the existence of "hybrid pericytes", cells in the vascular wall that express  possess VSMC features (like   class="ltx_Math" contenteditable="false" data-equation="\alpha">\(\alpha\)SMA yet data-equation="\alpha">\(\alpha\)SMA), but also  have an ovoid cell body that is characteristic of pericytes. Considering the conflicting in vivo studies, and the heterogeneity of pericytes found ex vivo, I hypothesize that a subset of pericytes, those with smooth muscle cell features, can regulate blood flow. To test this hypothesis, we must understand how structural features of pericytes and VSMCs are distributed along the vascular architecture, andthe locations  where these features overlap. Then Ultimately,  we must examine which structural features predict correlate with  the ability to regulate blood flow.