# Investigating the microvascular mechanisms of O2 supply-demand mismatch in small vessel disease using novel high-resolution optical imaging

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $736,716

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite intense research, we lack even the most basic understanding of how structural and functional changes
in small vessel diseases of the brain (SVD) are linked to tissue oxygenation, whether this results in tissue
hypoxia (O2 supply-demand mismatch), and how different microvascular segments contribute to this mismatch
in different brain areas. Leveraging our cutting-edge optical imaging tools for absolute pO2, blood flow, Ca2+
signaling, and microvascular morphology, and a clinically relevant CADASIL mouse model, we propose to
examine for the first time a causal link between microvascular dysfunction and O2 supply-demand mismatch.
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is
the most common monogenic inherited form of SVD leading to dementia, caused by mutations in Notch3.
Transgenic models of CADASIL recapitulate many clinical and histopathological hallmarks of the disease,
including early signs of SVD such as impaired CBF and functional hyperemic responses, and functional and
structural abnormalities in both arterioles and capillaries.
We will quantify absolute intravascular and tissue pO2, metabolic rate of O2 (CMRO2), CBF and capillary red
blood cell flux, and microvascular morphology, at rest and during functional brain activation, in both gray and
white matter, longitudinally over months, in unanesthetized CADASIL transgenic mice. Aim 1 will test whether
CADASIL causes age-dependent O2 supply-demand mismatch, manifested in islets of tissue hypoxia at rest or
during functional activation. Combining two-photon microscopy and optical coherence tomography (OCT), we
will test whether CADASIL leads to abnormal capillary red blood cell flux and increased capillary transit time
heterogeneity causing O2 supply-demand mismatch even before a reduction in absolute CBF becomes
manifest. Finally, we will examine whether O2 supply-demand mismatch can be corrected by genetic,
pharmacological, and immunological manipulations. Aim 2 will test whether CADASIL causes Ca2+
dysregulation in vascular smooth muscle and pericytes and whether it can be corrected by genetic,
pharmacological and immunological manipulations. Aim 3 will integrate the measurements from Aims 1 and 2
and construct a numerical model of oxygen advection and diffusion based on measured microvascular
morphology, reactivity, perfusion, and oxygenation. The model will relate structural and functional
microvascular changes to tissue O2 supply-demand mismatch, quantify the contribution and predict the limits of
the arteriolar and capillary compartments to support tissue oxygenation below which O2 supply-demand
mismatch develops. The model will thus shed light on all other SVDs (e.g. hypertension, amyloid). Altogether,
this proposal aims to fill significant gaps in our understanding of the mechanisms of microvascular dysfunction
in CADASIL, and will inform the vascular mechanisms of progressive neurodegeneration...

## Key facts

- **NIH application ID:** 10146502
- **Project number:** 5R01NS115401-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Cenk Ayata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $736,716
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146502

## Citation

> US National Institutes of Health, RePORTER application 10146502, Investigating the microvascular mechanisms of O2 supply-demand mismatch in small vessel disease using novel high-resolution optical imaging (5R01NS115401-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146502. Licensed CC0.

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