Microvascular patterning is controlled by fine-tuning the Akt signal.
We investigated the functions of Akt during vascular development and remodeling by using an inducible endothelial cell-specific driver of the dominant-active myrAkt. We found that sustained signaling in response to overexpression of myrAkt led to embryonic lethality, edema, and vascular malformations. In addition to the morphological malformations, the vascular phenotype was consistent with a failure in remodeling, such that the normal patterning and vessel hierarchy was disturbed. Examination of the well studied retinal vasculature during the remodeling phases revealed that transient expression of myrAkt was capable of altering the normal response to oxygen-induced remodeling without causing vascular malformations. These findings suggest that physiological levels of Akt signaling modulated microvascular remodeling and support the hypothesis that, although Akt may be required for vascular growth and homeostasis, appropriate down-regulation is also an essential aspect of normal vascular patterning.
Sun
Jing Fang
JF
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Phung
Thuy
T
Shiojima
Ichiro
I
Felske
Terri
T
Upalakalin
J Nalinee
JN
Feng
Dian
D
Kornaga
Tad
T
Dor
Talia
T
Dvorak
Ann M
AM
Walsh
Kenneth
K
Benjamin
Laura E
LE
D000818:Animals; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D012171:Retinal Vessels / Q000002:abnormalities / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000098:blood supply / Q000196:embryology
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt