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The role of Akt/protein kinase B in ...

Ackah, Eric.

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The role of Akt/protein kinase B in postnatal angiogenesis: Insights from Akt knockout mice.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The role of Akt/protein kinase B in postnatal angiogenesis: Insights from Akt knockout mice./
Author:	Ackah, Eric.
Description:	191 p.
Notes:	Adviser: William C. Sessa.
Contained By:	Dissertation Abstracts International67-04B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3214159
ISBN:	9780542651052

The role of Akt/protein kinase B in postnatal angiogenesis: Insights from Akt knockout mice.
Ackah, Eric.

The role of Akt/protein kinase B in postnatal angiogenesis: Insights from Akt knockout mice. - 191 p.

Adviser: William C. Sessa.

Thesis (Ph.D.)--Yale University, 2006.

Angiogenesis, the formation of new capillaries, is associated with normal processes such as wound healing and pathological conditions including tumor growth and diabetic retinopathy. It is also important in peripheral arterial occlusive conditions to minimize tissue necrosis associated with ischemia. Thus, understanding the mechanisms of angiogenesis is of therapeutic significance. Although the Akt/Protein Kinase B signaling pathway has been linked to vascular cell survival and migration, the roles of specific Akt isoforms in postnatal angiogenesis are not clear. The data presented here show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia-induced angiogenesis and severe peripheral vascular disease. Akt1-deficient mice also exhibit impaired vascular endothelial growth factor (VEGF)-induced angiogenesis. Analysis of gene expression shows that mRNA levels of the angiogenic growth factors VEGF and platelet-derived growth factor (PDGF) were reduced in the ischemic limbs of Akt1 knockout mice. In addition, ischemia-induced endothelial progenitor cell (EPC) mobilization was markedly reduced in Akt1 knockout mice, and EPCs isolated from Akt1 nulls, in contrast to those from wild type mice, did not improve blood flow. In endothelial cells, the loss of Akt1 was associated with impaired cell survival, proliferation and migration, as well as a reduction in phosphorylation of the Akt substrates endothelial nitric oxide synthase (eNOS), glycogen synthase kinase 3 (GSK-3) and the Forkhead transcription factor Foxo1. Both basal and VEGF-induced nitric oxide (NO) production were also markedly reduced in Akt1 knockout endothelial cells. Quantitative Western blot analysis showed that while both Akt1 and Akt2 were expressed in blood vessels, Akt1 was the predominant isoform in endothelial cells with Akt2 more abundant in fibroblasts. Reconstitution of Akt1 knockout cells with Akt2 completely restored Foxo1 and GSK3beta phosphorylation, but not eNOS phosphorylation or NO release. Consistent with this, in vitro kinase analysis showed that direct phosphorylation of eNOS on Serine 1179 and Serine 617 by Akt1 were more than 2 to 6-fold greater than that induced by Akt2. These results establish the Akt1 isoform as an important in vivo regulator of postnatal angiogenesis through multiple processes including blood flow control, EPC mobilization and function, cell migration and eNOS-NO signaling.

ISBN: 9780542651052Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

The role of Akt/protein kinase B in postnatal angiogenesis: Insights from Akt knockout mice.
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245 1 4 $a The role of Akt/protein kinase B in postnatal angiogenesis: Insights from Akt knockout mice.
300 $a 191 p.
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500 $a Source: Dissertation Abstracts International, Volume: 67-04, Section: B, page: 1932.
502 $a Thesis (Ph.D.)--Yale University, 2006.
520 $a Angiogenesis, the formation of new capillaries, is associated with normal processes such as wound healing and pathological conditions including tumor growth and diabetic retinopathy. It is also important in peripheral arterial occlusive conditions to minimize tissue necrosis associated with ischemia. Thus, understanding the mechanisms of angiogenesis is of therapeutic significance. Although the Akt/Protein Kinase B signaling pathway has been linked to vascular cell survival and migration, the roles of specific Akt isoforms in postnatal angiogenesis are not clear. The data presented here show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia-induced angiogenesis and severe peripheral vascular disease. Akt1-deficient mice also exhibit impaired vascular endothelial growth factor (VEGF)-induced angiogenesis. Analysis of gene expression shows that mRNA levels of the angiogenic growth factors VEGF and platelet-derived growth factor (PDGF) were reduced in the ischemic limbs of Akt1 knockout mice. In addition, ischemia-induced endothelial progenitor cell (EPC) mobilization was markedly reduced in Akt1 knockout mice, and EPCs isolated from Akt1 nulls, in contrast to those from wild type mice, did not improve blood flow. In endothelial cells, the loss of Akt1 was associated with impaired cell survival, proliferation and migration, as well as a reduction in phosphorylation of the Akt substrates endothelial nitric oxide synthase (eNOS), glycogen synthase kinase 3 (GSK-3) and the Forkhead transcription factor Foxo1. Both basal and VEGF-induced nitric oxide (NO) production were also markedly reduced in Akt1 knockout endothelial cells. Quantitative Western blot analysis showed that while both Akt1 and Akt2 were expressed in blood vessels, Akt1 was the predominant isoform in endothelial cells with Akt2 more abundant in fibroblasts. Reconstitution of Akt1 knockout cells with Akt2 completely restored Foxo1 and GSK3beta phosphorylation, but not eNOS phosphorylation or NO release. Consistent with this, in vitro kinase analysis showed that direct phosphorylation of eNOS on Serine 1179 and Serine 617 by Akt1 were more than 2 to 6-fold greater than that induced by Akt2. These results establish the Akt1 isoform as an important in vivo regulator of postnatal angiogenesis through multiple processes including blood flow control, EPC mobilization and function, cell migration and eNOS-NO signaling.
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