Abstract 636: Angiotensin II-Mediated Endothelial Cell Dysfunction Contributes to Adipocyte Stem Cell Dysfunction and Adiposity
Rationale: Crosstalk between perivascular adipose tissue and endothelial cells has been proposed to modulate vascular homeostasis. However, paracrine regulatory effects of the stressed endothelium on adipose tissue are relatively unknown.
Objective: We examined the hypothesis that redox mechanisms in endothelial cells can regulate adipocyte function, in a paracrine fashion, via suppression of the Wnt10b/β-catenin-dependent pathways.
METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with AngII (1-50 μM) in the absence and in the presence of the heme oxygenase (HO-1) inducer_cobalt protoporphyrin (CoPP)_or to HO-1 activity inhibitor_stannous mesoporphyrin (SnMP). Adipogenesis was then induced in mesenchymal stem cells, in the presence (10%) or absence of conditioned media (CM) from HUVECs.
Results: MSCs exposed to CM from AngII-treated HUVEC displayed enhanced adipogenesis (0.026±0.001 vs. 0.031±0.001, n=6, p<0.0405). This effect was reversed in MSCs supplemented with CM from HUVECs treated with AngII and CoPP (0.021±0.001, n=6, p<0.0024). This beneficial effect of CoPP in MSCs exposed to CM is reversed by SnMP (0.030±0.001, n=6, p<0.0462) and corroborates the ability of HO-1 in attenuating AngII-dependent adipocyte dysfunction. Complementary immunoblot analysis showed an attenuative effect of AngII on Wnt10b and β-catenin expression (p<0.05). Additionally, AngII enhanced the expression of adipogenic regulators including PPARY, CEBPα, and aP2, which was decreased by CoPP and increased by SnMP.
Conclusion: Our results show that EC dysfunction, as a result of treatment with AngII, contributes to increased adipogenesis in MSCs by the release of negative regulators of adipogenesis. We also show that up-regulation of antioxidant HO-1 ameliorates these effects of AngII. This novel observation suggests that paracrine crosstalk between HUVECs and adipocytes increases endothelial stress to affect adipocyte structure and function. These phenomena might contribute to the metabolic imbalance frequently encountered in conditions associated with chronic endothelial dysfunction and adiposity.
- © 2012 by American Heart Association, Inc.