Editors' ChoicePhysiology

Why Wounds Won’t Heal for Diabetics

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Sci. Signal.  25 Feb 2014:
Vol. 7, Issue 314, pp. ec54
DOI: 10.1126/scisignal.2005210

Endothelial cell migration is required to repair damage to blood vessels or to recover from injuries that require angiogenesis, and endothelial cells are dysfunctional in individuals with diabetes. Noting that the transcriptional coactivator PGC-1α promotes angiogenesis in skeletal muscle and heart, Sawada et al. examined the role of PGC-1α in endothelial cells. The expression of the gene encoding PGC-1α was increased in endothelial cells of mice with diet-induced or genetically induced type 2 diabetes and mice with streptozotocin (STZ)–induced type 1 diabetes and in cultured endothelial progenitor cells (EPCs) from diabetic patients. Endothelial cells from STZ-treated mice or db/db mice showed decreased migration, which correlated with higher mRNA abundance for PGC-1α. Endothelial cells from mice overexpressing PGC-1α showed decreased migration, an effect that also occurred in various endothelial cell types, including primary human endothelial colony-forming cells (ECFCs). The promigratory stimuli vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) can activate the extracellular signal–regulated kinase (ERK) and Akt pathways through their receptors, and ECFCs overexpressing PGC-1α showed decreased activation of Akt, but not of ERK, in response to treatment with VEGF or S1P. Notch signaling results in the formation of the Notch intracellular domain (NICD), a transcriptional regulator, which is generated through the action of matrix metalloproteases (MMPs) and γ-secretases on the Notch receptor. Notch signaling inhibits endothelial cell migration and sprouting angiogenesis. PGC-1α overexpression in human umbilical vein endothelial cells (HUVECs) stimulated Notch signaling, as indicated by increased NICD abundance and increased expression of Notch target genes. Capillary sprouting was reduced in aortic explants from mice overexpressing PGC-1α in endothelial cells, an effect that was rescued with a γ-secretase inhibitor. The abundance of the mRNA for the MMP ADAMTS10 was increased in heart endothelial cells from PGC-1α–overexpressing mice, lung endothelial cells from STZ-treated mice, EPCs from diabetic patients, and human dermal microvascular endothelial cells treated with high glucose. Knockdown of ADAMTS10 decreased Notch target gene expression and promoted migration in HUVECs. Endothelial cells from PGC-1α–/– mice showed increased migration, and aortic explants from these mice displayed increased capillary sprouting. Accordingly, the defective wound healing in STZ-treated mice and mice on a high-fat diet was improved by endothelial cell–specific ablation of PGC-1α and, conversely, mice that inducibly overexpressed PGC-1α in endothelial cells did not effectively heal from various forms of injury for which the repair processes require endothelial cell migration and angiogenesis. Thus, PGC-1α inhibition could attenuate endothelial cell dysfunction in diabetic individuals; however, such therapies would also block the pro-angiogenic effects of PGC-1α in skeletal muscle and heart.

N. Sawada, A. Jiang, F. Takizawa, A. Safdar, A. Manika, Y. Tesmenitsky, K.-T. Kang, J. Bischoff, H. Kalwa, J. L. Sartoretto, Y. Kamei, L. E. Benjamin, H. Watada, Y. Ogawa, Y. Higashikuni, C. W. Kessinger, F. A. Jaffer, T. Michel, M. Sata, K. Croce, R. Tanaka, Z. Arany, Endothelial PGC-1α mediates vascular dysfunction in diabetes. Cell Metab. 19, 246–258 (2014). [PubMed]