Switch in Laminin ß2 to Laminin ß1 Isoforms During Aging Controls Endothelial Cell Functions-Brief Report

Authors:
Wagner JUG1,2, Chavakis E3, Rogg EM1, Muhly-Reinholz M1, Glaser SF1,2, Günther S4, John D1, Bonini F1, Zeiher AM3,2, Schaefer L5, Hannocks MJ2, Boon RA1,2, Dimmeler S6,2.
In:
Source: Arterioscler Thromb Vasc Biol
Publication Date: ()
Issue: 38: 1170-1177
Cells used in publication:
Endothelial, umbilical vein, human (HUVEC)
Species: human
Tissue Origin: vein
Endothelial, coronary art, human (HCAEC)
Species: human
Tissue Origin: artery
Experiment


Abstract

OBJECTIVE:

Endothelial cells play important roles in tissue homeostasis and vascularization, a function that is impaired by aging. Here, we aim to decipher the role of the microenvironment underlying the impairment of endothelial cell functions by aging.

APPROACH AND RESULTS:

RNA sequencing of isolated cardiac endothelial cells derived from young and 18-month-old mouse hearts revealed that aging affects the endothelial expression of genes encoding extracellular matrix proteins, specifically the laminin ß1 (Lamb1) and laminin ß2 (Lamb2) chains. Whereas Lamb1 was upregulated, Lamb2 was decreased in endothelial cells in old mice compared with young controls. A similar change in expression patterns was observed after induction of acute myocardial infarction. Mimicking aging and injury conditions by plating endothelial cells on laminin ß1-containing laminin 411 matrix impaired endothelial cell adhesion, migration, and tube formation and augmented endothelial-to-mesenchymal transition and endothelial detachment compared with laminin 421, which contains the laminin ß2 chain. Because laminins can signal via integrin receptors, we determined the activation of ITGB1 (integrin ß1). Laminin 421 coating induced a higher activation of ITGB1 compared with laminin 411. siRNA-mediated silencing of ITGB1 reduced laminin ß2-dependent adhesion, suggesting that laminin ß2 more efficiently activates ITGB1.

CONCLUSIONS:

Mimicking age-related modulation of laminin ß1 versus ß2 chain expression changes the functional properties and phenotype of endothelial cells. The dysregulation of the extracellular matrix during vascular aging may contribute to age-associated impairment of organ function and fibrosis