Aortic Aneurysm Generation in Mice With Targeted Deletion of Integrin-Linked Kinase in Vascular Smooth Muscle Cells

作者：Shen Dongxiao; Li Jian; Lepore John J; Anderson Thomas J T; Sinha Sumita; Lin Alexander Y; Cheng Lan; Cohen Ethan David; Roberts Jesse D Jr; Dedhar Shoukat; Parmacek Michael S; Gerszten Robert E^*

来源：Circulation Research, 2011, 109(6): 616-U78.

DOI：10.1161/CIRCRESAHA.110.239343

• integrin-linked kinase
• smooth muscle cells
• aortic aneurysm
• actin cytoskeleton
• myocardin-related transcription factor-A

Rationale: Integrin-linked kinase (ILK) is located at focal adhesions and links the extracellular matrix (ECM) to the actin cytoskeleton via beta 1- and beta 3-integrins. ILK plays a role in the activation of kinases including protein kinase B/Akt and glycogen synthase kinase 3 beta and regulates cell proliferation, motility, and survival.
Objective: To determine the function of ILK in vascular smooth muscle cells (SMCs) in vivo.
Methods and Results: SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice were generated in which the Ilk gene was selectively ablated in SMCs. SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice survive to birth but die in the perinatal period exhibiting multiple vascular pathologies including aneurysmal dilatation of the aorta and patent ductus arteriosus (PDA). Defects in morphogenetic development of the aorta were observed as early as E12.5 in SM22Cre(+)Ilk(Fl/Fl) mutant embryos. By late gestation (E16.5 to 18.5), striking expansion of the thoracic aorta was observed in ILK mutant embryos. Histological analyses revealed that the structural organization of the arterial tunica media is severely disrupted with profound derangements in SMC morphology, cell-cell, and cell-matrix relationships, including disruption of the elastic lamellae. ILK deletion in primary aortic SMCs results in alterations of RhoA/cytoskeletal signaling transduced through aberrant localization of myocardin-related transcription factor (MRTF)-A repressing the transcription and expression of SMC genes, which are required for the maintenance of the contractile SMC phenotype.
Conclusions: These data identify a molecular pathway linking ILK signaling to the contractile SMC gene program. Activation of this pathway is required for morphogenetic development of the aorta and ductus arteriosus during embryonic and postnatal survival. (Circ Res. 2011;109:616-628.)

• 出版日期2011-9-2