Dataset Information

PGC-1? regulates normal and pathological angiogenesis in the retina.

ABSTRACT: Neovascular diseases of the eye are the most common causes of blindness worldwide. The mechanisms underlying pathological neovascularization in the retina remain incompletely understood. PGC-1? is a transcriptional coactivator that plays a central role in the regulation of cellular metabolism. In skeletal muscle, PGC-1? induces VEGFA expression and powerfully promotes angiogenesis, suggesting a similar role in other tissues. This study investigates the role of PGC-1? during normal and pathological vascularization in the retina. We show that PGC-1? induces the expression of VEGFA in numerous retinal cells, and that PGC-1? expression is strongly induced during postnatal retinal development, coincident with VEGFA expression and angiogenesis. PGC-1?(-/-) mice have a significant reduction of early retinal vascular outgrowth, and reduced density of capillaries and number of main arteries and veins as adults. In the oxygen-induced retinopathy model of retinopathy of prematurity, PGC-1? expression is dramatically induced in the inner nuclear layer of the retina, suggesting that PGC-1? drives pathological neovascularization. In support of this, PGC-1?(-/-) mice subjected to oxygen-induced retinopathy had decreased expression of VEGFA and were protected against pathological neovascularization. These results demonstrate that PGC-1? regulates VEGFA in the retina and is required for normal vessel development and for pathological neovascularization. The data highlight PGC-1? as a novel target in the treatment of neovascular diseases of the eye.

SUBMITTER: Saint-Geniez M

PROVIDER: S-EPMC3538026 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PGC-1α regulates normal and pathological angiogenesis in the retina.

Saint-Geniez Magali M Jiang Aihua A Abend Stephanie S Liu Laura L Sweigard Harry H Connor Kip M KM Arany Zoltan Z

The American journal of pathology 20121107 1

Neovascular diseases of the eye are the most common causes of blindness worldwide. The mechanisms underlying pathological neovascularization in the retina remain incompletely understood. PGC-1α is a transcriptional coactivator that plays a central role in the regulation of cellular metabolism. In skeletal muscle, PGC-1α induces VEGFA expression and powerfully promotes angiogenesis, suggesting a similar role in other tissues. This study investigates the role of PGC-1α during normal and pathologic ...[more]

PMID: 23141926

Similar Datasets

Project description:RationaleMechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle.ObjectiveTo test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.Methods and resultsHere, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease.ConclusionsPGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.

Project description:BackgroundThe airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens.MethodsBEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated.ResultsThe amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin.ConclusionsThe current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

Dataset Information

PGC-1? regulates normal and pathological angiogenesis in the retina.

Publications

PGC-1α regulates normal and pathological angiogenesis in the retina.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets