Visualizing TGF-β and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation

Background: The TGF-beta superfamily members Transforming Growth Factor-beta (TGF-beta/Activin) and Bone Morphogenetic Proteins (BMP) have been implicated in the pathogenesis of atherosclerosis. However, their role in human disease remains controversial. In this study we used Smad phosphorylation as a read out for TGF-beta and BMP signaling during the initiation, progression and (de) stabilization of human atherosclerotic disease. Material and methods: A systematic analysis was performed in 114 peri-renal aortic patches (stained with Movat Pentachrome, H&E, pSmad2, pSmad1,5,8 and PAI-1) covering the entire atherosclerotic spectrum (van Dijk, 2010). Immunostaining against T-cells (CD3) and monocytes and macrophages (CD68) was used to explore a putative association between TGF-beta and BMP signaling and vascular inflammation. Results: Smad phosphorylation was present within the normal arterial wall in approximately 10% of the endothelial cells and intimal smooth muscle cells. A significant increase in pSmad2 and pSmad1,5,8 positivity was found in non-progressive lesions (>50% positivity). No further increase or decrease was found in the progressive atherosclerotic lesions, vulnerable and stabilized lesions. No association was found between TGF-beta and BMP signaling and CD3 and CD68 expression, nor cap thickness. Conclusion: Activation of the TGF-beta and BMP pathways is an early event in atherosclerotic lesion formation. No significant relationships were found between Smad phosphorylation and vessel wall inflammation or plaque vulnerability.