# Transitional Segment Hypercontractility in Small Vessel Disease with Intracerebral Hemorrhage

> **NIH NIH F32** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $65,310

## Abstract

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 micr...

## Key facts

- **NIH application ID:** 9992441
- **Project number:** 1F32HL152576-01
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Nicholas Ryan Klug
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2020-05-21 → 2023-05-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992441

## Citation

> US National Institutes of Health, RePORTER application 9992441, Transitional Segment Hypercontractility in Small Vessel Disease with Intracerebral Hemorrhage (1F32HL152576-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9992441. Licensed CC0.

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