# Subendothelial Exosomes in Coronary Microvascular Dysfunction

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $554,889

## Abstract

Project Summary
Coronary microvascular dysfunction or disease (CMD) may lead to angina pectoris or acute coronary
syndrome (ACS) without obstructive coronary artery disease (CAD), which is considered as one of major
mechanisms of ischemia heart disease (IHD). However, the pathogenesis of CMD remains unclear. Based on
literature and our previous studies, we wondered whether exosomes or other microvesicles-mediated signaling
from endothelial cells (ECs) serve as a crucial mechanism mediating CMD because much thinner endothelium-
smooth muscle (EC-SM) space in small coronary arteries (CAs) or arterioles than large arteries may limit the
development of typical atherogenic pathology, but the exosome-carrying molecules may result in functional
abnormality in these small coronary arteries. Our preliminary studies indeed demonstrated that exosomes were
increasingly secreted into subendothelial space in small coronary arteries in mice fed the Western diet (WD)
and that deletion of lysosomal acid ceramidase (AC) in coronary ECs from Asah1fl/fl/ECcre mice, a strain of EC-
specific AC gene knockout mice (Asah1 is mouse gene code of AC) resulted in accumulation or trapping of
exosomes in the EC-SM space, leading to CMD-mediated myocardial ischemia without atherosclerosis and
obstructive CAD. The present grant proposal will test a central hypothesis that endothelium-derived exosomes
regulated by lysosomal AC-mediated sphingolipid metabolism plays a crucial role in the control of small CA
function and that subendothelial exosome accumulation is critically implicated in the pathogenesis of CMD. To
test this hypothesis, three Specific Aims are proposed. Specific Aim 1 will determine whether exosome
secretion from coronary arterial ECs is fine controlled by lysosomal AC activity and whether the deficiency of
this AC regulation causes subendothelial accumulation of exosomes in small CAs of Asah1fl/fl/ECcre mice,
leading to CMD and myocardial ischemia without atherosclerosis and obstructive CAD. Specific Aim 2
attempts to test whether lysosomal AC-mediated sphingolipid signaling regulates lysosome trafficking to and
fusion with multivesicular bodies (MVBs) to limit exosome secretion from ECs and whether pathologically
released exosomes from ECs with gene deletion from Asah1fl/fl/ECcre mice induce dysfunction of coronary
arterial SMCs. In Specific Aim 3, we will address whether the AC regulation of lysosome trafficking and
exosome secretion from coronary ECs are attributed to its action on lysosomal TRPML1 channel activity and
associated Ca2+ release and whether the deficiency of this regulatory mechanism leads to subendothelial
exosome accumulation and CMD. To our knowledge, these proposed studies will represent the first effort to
investigate the pathogenic role of subendothelial exosomes in CMD and consequent myocardial ischemia and
the findings will provide new insights into the pathogenesis of CMD and IHD without atherosclerosis or
obstructive CAD.

## Key facts

- **NIH application ID:** 10234472
- **Project number:** 2R01HL075316-13
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PinLan Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $554,889
- **Award type:** 2
- **Project period:** 2004-03-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234472

## Citation

> US National Institutes of Health, RePORTER application 10234472, Subendothelial Exosomes in Coronary Microvascular Dysfunction (2R01HL075316-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10234472. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*