# Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $769,034

## Abstract

Microvascular inflammation and dysfunction is widely believed to be the underlying cause of many of the clinical
complications of diabetes and metabolic disease including renal and heart failure, neuropathy, and maculae
degeneration. Much is known regarding mechanisms by which leucocytes and endothelial cells (EC) contribute
to this process. However, in spite of compelling evidence that abnormal investment of perivascular smooth
muscle cells and pericytes (SMC-Pc) is a common feature of microvascular disease pathogenesis, little is known
regarding the role or mechanisms by which these cells might contribute to this process. Inadequate SMC-Pc
investment of nascent EC tubes is also a major rate-limiting factor in attempts to induce therapeutic angiogenesis
to augment wound repair or recovery from ischemic injury. Indeed, this includes many failed VEGF clinical trials
where there is robust formation of EC tubes but failure to form a mature functional vascular network with efficient
blood delivery because vessels lack SMC-Pc coverage and are dilated and leaky. Studies in this proposal will
test the overall hypothesis that the stem cell pluripotency genes Oct4 and Klf4 play a critical role in
regulating the plasticity of microvascular SMC-Pc during vascular remodeling in response to injury and
hypoxia, as well as development of microvascular inflammation and dysfunction associated with
metabolic disease. Consistent with this hypothesis, initial studies by our lab using unique SMC-Pc specific
eYFP lineage tracing mice +/- simultaneous conditional knockout (KO) of Oct4 exclusively in SMC-Pc showed
that Oct4 expression within SMC-Pc is required for functional angiogenesis in corneal burn and hind limb
ischemia models. Moreover, we present exciting new data in this revised application showing that Klf4
expression within microvascular SMC-Pc plays a critical role in regulating the innate metabolic and inflammatory
properties of the mesenteric microvascular network and surrounding adipose tissue even in non-hyperlipidemic
mice. Aim 1 will test the hypothesis that activation of Oct4 within microvascular SMC-Pc is a key rate-limiting
step in both normal and dysfunctional angiogenesis including that associated with diet-induced obesity
(DIO)/metabolic disease. Aim 2 will determine mechanisms that regulate Oct4 re-activation within microvascular
SMC-Pc including testing the hypothesis that it is hypoxia, NFκB, and Klf4-dependent. Aim 3 will test the
hypothesis that Klf4-dependent phenotypic transitions of microvascular SMC-Pc play a key protective role in
regulating the innate metabolic and inflammatory properties of normal adipose tissue and that loss of these
protective effects contribute to global microvascular inflammation/dysfunction during development of metabolic
disease. Studies may lead to novel therapeutic approaches for enhancing therapeutic angiogenesis and/or treating and
preventing microvascular disease complications of diabetes and metabolic dise...

## Key facts

- **NIH application ID:** 9919376
- **Project number:** 5R01HL135018-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Gary K Owens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $769,034
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919376

## Citation

> US National Institutes of Health, RePORTER application 9919376, Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction (5R01HL135018-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9919376. Licensed CC0.

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