Loss of endothelial barrier integrity in mice with conditional ablation of podocalyxin (Podxl) in endothelial cells.
Podocalyxin (Podxl) has an essential role in the development and function of the kidney glomerular filtration barrier. It is also expressed by vascular endothelia but perinatal lethality of podxl(-/-) mice has precluded understanding of its function in adult vascular endothelial cells (ECs). In this work, we show that conditional knockout mice with deletion of Podxl restricted to the vascular endothelium grow normally but most die spontaneously around three months of age. Histological analysis showed a nonspecific inflammatory infiltrate within the vessel wall frequently associated with degenerative changes, and involving vessels of different caliber in one or more organs. Podxl-deficient lung EC cultures exhibit increased permeability to dextran and macrophage transmigration. After thrombin stimulation, ECs lacking Podxl showed delayed recovery of VE-cadherin cell contacts, persistence of F-actin stress fibers, and sustained phosphorylation of the ERM complex and activation of RhoA, suggesting a failure in endothelial barrier stabilization. The results suggest that Podxl has an essential role in the regulation of endothelial permeability by influencing the mechanisms involved in the restoration of endothelial barrier integrity after injury.
Department of Cellular and Molecular Medicine, Centre of Biological Research-CIB, CSIC, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
Angélica
A
Horrillo
Department of Cellular and Molecular Medicine, Centre of Biological Research-CIB, CSIC, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
Gracia
G
Porras
Department of Cellular and Molecular Medicine, Centre of Biological Research-CIB, CSIC, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
Matilde S
MS
Ayuso
Department of Cellular and Molecular Medicine, Centre of Biological Research-CIB, CSIC, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. Electronic address: cgmanchon@cib.csic.es.
Consuelo
C
González-Manchón
D000818:Animals; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000378:metabolism*; D005838:Genotype; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D012795:Sialoglycoproteins / Q000378:metabolism*
D012795:Sialoglycoproteins; C001643:podocalyxin
Endothelial cell; Inflammation; Podocalyxin; Vascular permeability