title: Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure.
abstract: Big mitogen-activated protein kinase 1 (BMK1), also known as ERK5, is a member of the MAPK family. Genetic ablation of BMK1 in mice leads to embryonic lethality, precluding the exploration of pathophysiological roles of BMK1 in adult mice. We generated a BMK1 conditional mutation in mice in which disruption of the BMK1 gene is under the control of the inducible Mx1-Cre transgene. Ablation of BMK1 in adult mice led to lethality within 2-4 weeks after the induction of Cre recombinase. Physiological analysis showed that the blood vessels became abnormally leaky after deletion of the BMK1 gene. Histological analysis revealed that, after BMK1 ablation, hemorrhages occurred in multiple organs in which endothelial cells lining the blood vessels became round, irregularly aligned, and, eventually, apoptotic. In vitro removal of BMK1 protein also led to the death of endothelial cells partially due to the deregulation of transcriptional factor MEF2C, which is a direct substrate of BMK1. Additionally, endothelial-specific BMK1-KO leads to cardiovascular defects identical to that of global BMK1-KO mutants, whereas, surprisingly, mice lacking BMK1 in cardiomyocytes developed to term without any apparent defects. Taken together, the data provide direct genetic evidence that the BMK1 pathway is critical for endothelial function and for maintaining blood vessel integrity.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hayashi
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Brian
authors.initials: B
authors.lastname: Eliceiri
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D002470:Cell Survival; D042783:Endothelial Cells / Q000502:physiology*; D005313:Fetal Death / Q000209:etiology; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000502:physiology; D011995:Recombination, Genetic
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases