# Role of endothelial and progenitor cell bioenergetics-cytoskeletal machinery in diabetic angiopathies

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $397,500

## Abstract

ABSTRACT
Diabetics suffer defective angiogenesis as a long-term complication and consequently a high propensity to
develop critical limb ischemia (CLI), the leading cause of limb amputation worldwide. This is due, in significant
part, to the deteriorated capacity of diabetic endothelial cells (ECs) and bone marrow-derived angiogenic cells,
also called endothelial progenitor cells (EPCs) to properly elaborate needed blood vessels in ischemic areas.
Lack of knowledge as to how this occurs has hampered therapeutic opportunities for CLI, including adoptive
therapies with autologous EPCs. PPARγ-coactivator (PGC)-1α is a versatile regulator of gene transcription that
coordinates broad metabolic programs in numerous tissues. The new and critical role for endothelial PGC-1α is
now emerging. Diabetes induces PGC-1α in mouse ECs and human EPCs, which in turn activates Notch
pathway that powerfully renders ECs resistant to VEGF. Ablation of EC PGC-1α in diabetic mice dramatically
rescues the full angiogenic capacity, which highlights considerable promise of targeting PGC-1α-Notch axis to
treat diabetic CLI. However, the significance of EC PGC-1α in diabetes is just beginning to be understood.
Deeper knowledge of how exactly this pathway blunts EC and EPC functions is imperative to fully explore its
therapeutic potential, since PGC-1α and Notch are expressed widely and mediate distinct, sometimes opposing
effects among cell types. Burgeoning evidence indicates that ECs are highly glycolytic comparable to tumor
cells, and that EC energy metabolism is the key mediator of sprouting angiogenesis in response to VEGF. In
this proposal, we hypothesize that persistent angiogenic impairment of diabetes is, at least in part, mediated by
PGC-1α/Notch-dependent alteration of cellular machineries that coordinate cytoskeleton with bioenergetics in
ECs and EPCs, and that this mechanism is independent of previously recognized mediators of diabetic vascular
dysfunction such as reactive oxygen species. Indeed, our preliminary findings identify novel downstream
effectors of PGC-1α/Notch axis that strongly support our hypothesis, and that this regulator is surprisingly
dispensable for health but required for diseases progression. This provides answers to many questions
regarding the PGC-1α angiostatic mechanism, and opens avenues to develop safe and efficacious therapeutics
for diabetic angiopathy that circumvent possible unwanted effects of targeting PGC-1α/Notch. Our hypothesis
would thus be of translational relevance to innovate therapies, including gene delivery and adoptive EPCs
transplantation, to salvage intractable dysfunction of ECs and EPCs in diabetes that causes angiogenic failure
and CLI. Our concept would also provide clues to strategizing how to intervene in cell metabolism and
cytoskeleton to develop therapeutics. The major goal of this proposal is to address this possibility.

## Key facts

- **NIH application ID:** 9895845
- **Project number:** 5R01HL136458-04
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Naoki Sawada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2017-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895845

## Citation

> US National Institutes of Health, RePORTER application 9895845, Role of endothelial and progenitor cell bioenergetics-cytoskeletal machinery in diabetic angiopathies (5R01HL136458-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895845. Licensed CC0.

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