Saturday, November 23, 2024
11/23/2024
Small vessel disease (SVD) is characterized by abnormalities in/around small perforating brain vessels. Many ischemic events and most intracerebral hemorrhages (ICH) are due to SVD, where hemorrhage leads to higher rates of mortality and severe disability. Presumably these events lead to deteriorating brain function. Indeed, SVDs account for ~45% of dementias. Small contractile vessels contain diverse anatomical and physiological characteristics. As small arterioles branch to form capillary networks they form a distinguishable contractile transitional segment. This transitional segment contains mural cells with distinct morphological and molecular characteristics compared to traditional arteriolar smooth muscle cells (SMCs). Preliminary data suggest that in healthy vessels these mural cells display distinct excitation-contraction coupling mechanisms compared to traditional SMCs. Moreover, in our animal model of SVD with ICH, which recapitulates the salient features of sporadic SVD with ICH, there is pronounced transitional segment “hypermuscularization” (increased mural cell number, higher content of contractile proteins, and increased contractility). Arterioles of these same animals undergo SMC degeneration, a seemingly opposite effect. Other severe forms of SVD demonstrate SMC degeneration but do not typically hemorrhage. This “hypermuscularization” may be a defining feature of sporadic and genetic SVD with ICH. I hypothesize transitional segment mural cells regulate blood flow through mechanisms distinct from arteriolar SMCs. I also propose these mural cells become distinctly hypercontractile in SVD with ICH. This hypothesis will be tested using two aims. First, I will elucidate mechanisms of pressure- induced constriction of transitional segments. I will test whether physiological constriction of transitional segment mural cells relies on functionally distinct mechanisms compared to arteriolar SMCs. I will probe known ion channels and calcium release pathways for distinguishing excitation-contraction coupling mechanisms. Second, I will determine mechanisms mediating transitional segment hypercontractily in an animal model of SVD with ICH. Here, I will test whether transitional segments of SVD animals with ICH have increased contractility in response to physiological pressure increases. I will probe excitation-contraction coupling pathways in wild type and diseased transitional segment mural cells to identify which are specifically altered in SVD with ICH. Both aims will utilize the pressurized retina preparation, isolated mural cell electrophysiology, and in vivo brain imaging in combination with genetically-encoded Ca2+ indicator mice. This research will take place in the highly productive vascular physiology/pharmacology laboratory of Dr. Mark Nelson at the University of Vermont. I will conduct electrophysiology and apply multiple imaging modalities (high-speed/resolution spinning disk confocal, multiphoton, ultra-speed sCMOS widefield microscopy) to live cells, tissues, and whole animals. Additionally, I will participate in weekly journal clubs and lab meetings. I will regularly travel domestically and internationally in order disseminate promising findings at conferences or to collaborate in colleagues’ laboratories.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
