Abstract MP02: Angiotensin II Mediates Microvascular Rarefaction In Vivo and Exacerbates Endothelial-To-Mesenchymal Transition In Vitro
Cardiac fibrosis accompanies numerous cardiovascular diseases (CVD) such as hypertension and myocardial infarction and increases myocardial stiffness leading to contractile dysfunction. Recently, endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to myocardial fibrosis. EndMT describes a process by which endothelial cells transform into mesenchymal cells such as fibroblasts and has been implicated in many fibrotic diseases. Angiotensin II (AngII) plays a key role in myocardial fibrosis and has been associated with the activation of fibroblasts to myofibroblasts and an increase in myocardial collagen deposition. Here, we assessed the role of AngII in capillary loss and EndMT in vivo and in vitro.
C57BL/6J mice were infused with H2O (control) or 24μg/kg/hr AngII for 4 weeks. Mice infused with AngII developed significant cardiac fibrosis characterised by the deposition of collagen I (2.5-fold vs. control; p<0.05) and III (1.9-fold vs. control; p<0.05). Capillary density was assessed by CD31 immunohistochemistry and revealed significant vascular rarefaction (control 2161±111 vs. AngII 838±132 capillaries/mm2; p<0.05). To investigate whether AngII can induce EndMT in vitro, human coronary artery endothelial cells were stimulated with 10ng/mL TGFβ1 alone or in combination with 1μM AngII for 10 days. AngII significantly enhanced TGFβ1-induced gene expression of α-smooth muscle actin (TGFβ1 1.8-fold; TGFβ1±AngII 4.3-fold vs. control; p<0.05) and collagen I (TGFβ1 9.2-fold; TGFβ1+AngII 30.2-fold vs. control; p<0.05). Concomitantly, AngII significantly increased α-smooth muscle actin protein expression (TGFβ1 3.9-fold; TGFβ1+AngII 23.6-fold vs. control; p<0.05) and significantly decreased CD31 expression (TGFβ1 0.9-fold; TGFβ1+AngII 0.7-fold vs. control; p<0.05), suggesting AngII acts in concert with TGFβ1 to enhance conversion of endothelial cells to myofibroblasts. Further studies investigating the underlying mechanism, including the role of the Smad pathway, are ongoing.
These results demonstrate that AngII induces vascular rarefaction in vivo and potentiates TGFβ1-induced EndMT in vitro. Understanding the molecular basis for these observations may help to identify new therapeutic options in CVD.
Author Disclosures: K. Nather: None. M. Flores-Muñoz: None. R.M. Touyz: None. C.M. Loughrey: None. S.A. Nicklin: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; British Heart Foundation PhD Studentship funded this research.
- © 2015 by American Heart Association, Inc.