Specific Aims

Goals of the proposed research

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. 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. While 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 the elements of the cerebrovasculature that can regulate blood flow under non-pathological conditions.

class="ltx_title_subsection">Hypothesis

However, class="ltx_title_subsection">Hypothesis

Pericytes are by definition juxtaposed to the vascular lumen, placing them in a perfect position to control capillary blood flow. However, in vivo investigations of the capacity of pericyte-laden capillaries to regulate blood flow provide opposing conclusions: one study claims that capillaries lined with pericytes can regulate cerebral blood flow, whereas another concluded that only arterioles lined with VSMCs can control blood flow, and not capillaries lined with pericytes. Each of these studies utilized a different definition of pericytes, adding Adding to the uncertainty of which cerebrovascular elements regulate blood flow in vivo. flow in vivo, these studies defined pericytes differently. These conflicting results and definitions could be explained by the existence of a subpopulation of pericytes that is capable of controlling blood flow. Ineed, ex vivo studies from our lab and others have shown that only pericytes near arterioles and venules, but not the pericytes in the middle of the capillary bed, are equipped with contractile proteins and other features that are presumably necessary for blood flow regulation. In light of the conflicting in vivo results, and the heterogeneity of pericytes found ex vivo, we hypothesize that pericytes near penetrating vessels that express contractile proteins can regulate blood flow.

Could indicate that a subpopulation of

showing that cerebral, blood flow regulation only exists on vessels that are within four branchpoints of the penetrating arteriole, matching the distribution of the expression of alpha smooth muscle actin ( ( class="ltx_Math" contenteditable="false" data-equation="\alpha">\(\alpha\)SMA), the primary contractile protein in cerebral blood vessels.

A systematic characterization of where contractile ability exists has not been performed.

A unifying hypothesis would thus be that the population of contractile pericytes overlaps with the population of pericytes expressing class="ltx_Math" contenteditable="false" data-equation="\alpha">\(\alpha\)SMA

Specific Aims

Aims

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.