Exp Mol Med.  2012 Mar;44(3):225-235. 10.3858/emm.2012.44.3.017.

AKAP12 regulates vascular integrity in zebrafish

Affiliations
  • 1NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea. qwonkim@snu.ac.kr
  • 2Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea.
  • 3Korea Basic Science Institute Chuncheon Center, Chuncheon 210-701, Korea.
  • 4School of Dentistry, Pusan National University, Yangsan 626-770, Korea.
  • 5Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
  • 6College of Pharmacy, Keimyung University, Daegu 704-701, Korea.
  • 7Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan.
  • 8Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, Korea.

Abstract

The integrity of blood vessels controls vascular permeability and extravasation of blood cells, across the endothelium. Thus, the impairment of endothelial integrity leads to hemorrhage, edema, and inflammatory infiltration. However, the molecular mechanism underlying vascular integrity has not been fully understood. Here, we demonstrate an essential role for A-kinase anchoring protein 12 (AKAP12) in the maintenance of endothelial integrity during vascular development. Zebrafish embryos depleted of akap12 (akap12 morphants) exhibited severe hemorrhages. In vivo time-lapse analyses suggested that disorganized interendothelial cell-cell adhesions in akap12 morphants might be the cause of hemorrhage. To clarify the molecular mechanism by which the cell-cell adhesions are impaired, we examined the cell-cell adhesion molecules and their regulators using cultured endothelial cells. The expression of PAK2, an actin cytoskeletal regulator, and AF6, a connector of intercellular adhesion molecules and actin cytoskeleton, was reduced in AKAP12-depleted cells. Depletion of either PAK2 or AF6 phenocopied AKAP12-depleted cells, suggesting the reduction of PAK2 and AF6 results in the loosening of intercellular junctions. Consistent with this, overexpression of PAK2 and AF6 rescued the abnormal hemorrhage in akap12 morphants. We conclude that AKAP12 is essential for integrity of endothelium by maintaining the expression of PAK2 and AF6 during vascular development.

Keyword

AKAP12 protein, human; disease models, animal; hemorrhage; hemostatic disorders; MLLT4 protein, human; PAK2 protein, human; zebrafish

MeSH Terms

A Kinase Anchor Proteins/*genetics/metabolism
Animals
Blood Vessels/abnormalities/*embryology/metabolism
Cell Cycle Proteins/genetics/metabolism
Down-Regulation
Embryo, Nonmammalian/abnormalities/*blood supply/embryology/metabolism
Gene Deletion
*Gene Expression Regulation, Developmental
Hemorrhage/*embryology/genetics/metabolism
Human Umbilical Vein Endothelial Cells
Humans
Intercellular Junctions/genetics/metabolism/ultrastructure
Kinesin/genetics/metabolism
Myosins/genetics/metabolism
Zebrafish/*embryology/genetics
p21-Activated Kinases/genetics/metabolism
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