Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Profound metabolic changes occur during ischemia, often leading to cell and organ death. The elicitation of new blood vessels, in an effort to mitigate ischemic damage, is part of a critical cellular and tissue response to ischemia. How metabolic activity and vascular homeostasis are coordinated, however, remains poorly understood. We have uncovered a novel pathway that regulates neovascularization in response to ischemia. Integral to this pathway are two transcriptional coactivators, PGC-1a (ppargc1a) and its close relative PGC-1? (ppargc1b). These proteins are well-known, powerful regulators of mitochondria and other metabolic processes. These coactivators thus directly link oxidative metabolism to angiogenesis, and they potentially coordinate the delivery of oxygen and substrates with their consumption. The identification of this novel angiogenic pathway raises a number of critical questions. The mechanism by which PGC-1a responds to ischemia remains unknown. The molecular mechanisms by which the PGC-1 coactivators regulate angiogenesis also remain incompletely defined. And finally, whether and how the PGC-1 coactivators can protect against limb ischemia in the adult needs further investigation. We propose here to examine these questions in close detail, both in cell culture and in intact animals. A number of genetic mouse models will be used, as well as well-established mouse models of limb ischemia and angiogenesis. The major goal of this proposal is to understand the molecular means by which PGC-1a and ? regulate angiogenesis. Investigating whether and how alterations in PGC-1a and/or ? can modulate angiogenesis may set the stage for the development of new classes of therapeutic drugs to treat ischemic diseases.

Public Health Relevance

Occlusion of blood vessels in the heart, brain, or limbs is a leading cause of death worldwide. The creation of new blood vessels in response to such events can be critical to tissue function and survival. We have uncovered a novel pathway that regulates the formation of new blood vessels. We propose here to examine this new pathway in close detail. These investigations may set the stage for the development of new classes of therapeutic drugs for ischemic diseases, as well as other diseases in which the formation of new blood vessels can be critical.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094499-03
Application #
8269059
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$430,650
Indirect Cost
$183,150
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Thom, Robyn; Rowe, Glenn C; Jang, Cholsoon et al. (2014) Hypoxic induction of vascular endothelial growth factor (VEGF) and angiogenesis in muscle by truncated peroxisome proliferator-activated receptor ? coactivator (PGC)-1?. J Biol Chem 289:8810-7
Chan, Mun Chun; Arany, Zolt (2014) The many roles of PGC-1? in muscle--recent developments. Metabolism 63:441-51
Rowe, Glenn C; Raghuram, Srilatha; Jang, Cholsoon et al. (2014) PGC-1? induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 115:504-17
Sawada, Naoki; Jiang, Aihua; Takizawa, Fumihiko et al. (2014) Endothelial PGC-1? mediates vascular dysfunction in diabetes. Cell Metab 19:246-58
Rowe, Glenn C; Safdar, Adeel; Arany, Zolt (2014) Running forward: new frontiers in endurance exercise biology. Circulation 129:798-810
Hilfiker-Kleiner, Denise; Arany, Zolt (2014) Focus on pregnancy-mediated heart and vascular disease. Cardiovasc Res 101:543-4
Rowe, Glenn C; Arany, Zoltan (2014) Genetic models of PGC-1 and glucose metabolism and homeostasis. Rev Endocr Metab Disord 15:21-9
Liu, Laura X; Arany, Zolt (2014) Maternal cardiac metabolism in pregnancy. Cardiovasc Res 101:545-53
Chan, Mun Chun; Rowe, Glenn C; Raghuram, Srilatha et al. (2014) Post-natal induction of PGC-1? protects against severe muscle dystrophy independently of utrophin. Skelet Muscle 4:2
Rowe, Glenn C; Patten, Ian S; Zsengeller, Zsuzsanna K et al. (2013) Disconnecting mitochondrial content from respiratory chain capacity in PGC-1-deficient skeletal muscle. Cell Rep 3:1449-56

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