Lymphangiogenesis in aortic valve stenosis鈥擭ovel regulatory roles for valvular myofibroblasts and mast cells

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• 作者：Suvi Syvä ; ranta^a ; Satu Helske^a ; ^b ; Jani Lappalainen^a ; Markku Kupari^b ; Petri T. Kovanen^a ; ^{petri.kovanen@wri.fi}
• 关键词：Aortic valve stenosis ; Lymphangiogenesis ; Mast cells ; Myofibroblasts ; Vascular endothelial growth factor C
• 刊名：Atherosclerosis
• 出版年：2012
• 期刊代码：28_00219150
• 类别：med
• 出版时间：April, 2012
• 卷：221
• 期：2
• 页码：366-374
• 文件大小：912 K

摘要

Objective

To investigate mechanisms of lymphangiogenesis in aortic valve stenosis (AS).

Methods

Lymphatic vessels were visualized with LYVE-1 staining in 20 control, 5 sclerotic, and 40 stenotic human aortic valves. Vascular endothelial growth factors (VEGFs) VEGF-C and VEGF-D, and their lymphangiogenic receptor VEGFR-3, and the angiogenic VEGFR-2 were analysed by quantitative real-time PCR and immunohistochemistry. Cultured myofibroblasts derived from human stenotic aortic valves, and cultured human mast cells were used to study VEGF-C regulation, and VEGF-C and VEGF-A were quantified from cell culture media by enzyme immunoassays.

Results

Lymphatic vessels, VEGF-C, VEGF-D, VEGFR-3 and VEGFR-2 all were present in the aortic valves. In AS, the number of lymphatic vessels and the expression of VEGF-D, VEGFR-3, and VEGFR-2 were increased. Moreover, the numbers of lymphatic vessels correlated positively with those of neovessels (r = 0.525, p = 0.001) and mast cells (r = 0.374, p = 0.017). Cultured valvular myofibroblasts produced VEGF-C, and addition of tumour necrosis factor alpha (TNF-伪) to the cells augmented its secretion. In contrast, proteases released by activated human mast cells degraded VEGF-C.

Conclusion

These results show that lymphangiogenesis is induced in advancing AS. Furthermore, valvular myofibroblasts and activated mast cells were identified as novel regulators of lymphangiogenesis in aortic valves.