Abstract
Extracellular matrix (ECM) composition and regulation is an essential component of coronary collateral growth (CCG). The ECM serves several functions which include mechanical and structural support, cell‐to‐cell communication, and regulation of cell mobility and phenotype. Laminin is a major component of the ECM. In the metabolic syndrome, the ECM composition is altered. In this study, we investigated the role of laminin and its binding to the β6 integrin in the regulation of CCG in response to repetitive ischemia (RI), and cellular processes involved in CCG. Coronary blood flow in Sprague‐Dawley (SD) or metabolic syndrome rats (JCR:LA‐cp, JCR), was measured in the collateral (CZ) and normal zone (NZ) of the heart using microspheres. Collateral‐dependent blood flow in JCR rats was impaired compared to SD rats (CZ/NZ flow ratio was 0.11±0.03 in JCR vs. 0.85±0.04 in SD), which correlated with decreased expression of laminin (~5 fold) and of the β6 integrin (~6 fold) in JCR animals. Administration of blocking‐antibodies against laminin or the β6 integrin in SD rats completely blocked CCG and decreased each other's expression, respectively. Furthermore, both laminin and β6 integrin expression were increased in endothelial cells (ECs) subjected to cycles of hypoxia‐hyperoxia‐normoxia to mimic RI vs. ECs cultured in normoxia. Blocking antibodies against laminin or the β6 integrin significantly impaired EC proliferation, migration and tube formation (~2–2.5 fold). TGF‐β signaling through Smad2/3 and leading to MMP 2/9 production, which is required for successful CCG, was also impaired (90%). Accordingly, TGF‐β receptor inhibition completely blocked CCG. Taken together, these results point to an important TGF‐β‐mediated pathway which promotes CCG and the activation of which is dependent on expression and the interaction between laminin and the β6 integrin.Support or Funding InformationSupport: NIH R01 HL093052This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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