# miR-615, AKT/eNOS signaling, and angiogenesis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $685,606

## Abstract

Ischemic cardiovascular disease (CVD) due to atherosclerotic occlusion of the arteries to the heart, legs, or
brain is associated with considerable morbidity, mortality, and health care expenditure in the United States.
The induction and orchestration of new blood vessels is critical for tissue repair in response to injury such as
myocardial infarction or peripheral artery disease (PAD). In response to pro-angiogenic stimuli, vascular
endothelial cells (ECs) are activated to migrate and proliferate to form primary capillaries. However, despite the
importance of ECs in neoangiogenesis, our understanding of the mechanisms regulating this process remains
poorly understood. Emerging studies indicate that the inability of angiogenic growth factors to stimulate
angiogenesis is likely due to impaired angiogenic signaling and not due to deficiency in these growth factors.
 MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs capable of repressing gene
expression by base pairing to the 3' untranslated regions (3'-UTRs) of mRNA targets and are involved in a
variety of pathophysiological processes in cardiovascular biology, though their function in angiogenesis and
angiogenic signaling pathways remains poorly defined. We undertook a microarray profiling approach of
plasma from subjects with ischemic CVD and identified that miR-615-5p expression is increased by ischemia
and reduced in response to pro-angiogenic stimuli–observations that are recapitulated in both mice and human
ischemic paradigms in vivo. Preliminary and published gain and loss-of-function studies reveal that miR-615-5p
overexpression markedly impaired EC proliferation, migration, and network tube formation in matrigel, whereas
blockade of miR-615-5p had the opposite effects. Mechanistically, using unbiased transcriptomic profiling, we
find that miR-615-5p suppressed EC proliferation and binding to 2 unique targets–RASSF2 and IGF2–in their
3'-UTRs and reduced their expression, an effect that selectively regulated the AKT/eNOS signaling pathway in
ECs. Finally, systemic intravenous administration of miR-615-5p inhibitors increased blood vessel formation
and reduced infarct size and improved blood flow recovery in ischemic legs compared to mice that received
scrambled control anti-miR injections. These observations provide the foundation for the central hypothesis
that miR-615-5p may serve as a critical regulator of EC proliferation and angiogenic responses. To better
understand the precise role of miR-615-5p in AKT/eNOS signaling and angiogenesis, we will in Aim1 delineate
the upstream mechanisms governing miR-615-5p expression in ECs. In Aim2, we will determine the molecular
basis for miR-615-5p's ability to regulate AKT/eNOS signaling and EC functions critical to angiogenesis. In
Aim3, we will explore the effect of altering miR-615-5p expression in the microvasculature on acute and
chronic experimental ischemic injury. The results of these studies will provide insights regarding mi...

## Key facts

- **NIH application ID:** 9973357
- **Project number:** 1R01HL148207-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MARK W FEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $685,606
- **Award type:** 1
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973357

## Citation

> US National Institutes of Health, RePORTER application 9973357, miR-615, AKT/eNOS signaling, and angiogenesis (1R01HL148207-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973357. Licensed CC0.

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