Serotonin potentiates transforming growth factor-beta3 induced biomechanical remodeling in avian embryonic atrioventricular valves.
Serotonin potentiates transforming growth factor-beta3 induced biomechanical remodeling in avian embryonic atrioventricular valves.
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DOI：
10.1371/journal.pone.0042527
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Butcher JT
中科院分区：
文献类型：
--
作者：
Buskohl PR;Sun MJ;Thompson RP;Butcher JT
胚胎心脏瓣膜原基（垫）保持单向血流在发展过程中，尽管越来越苛刻的机械环境。近年来的研究表明，房室垫在妊娠期间发生了变化，但其分子机制尚不清楚。转化生长因子-β（TGFβ）和5-羟色胺（5-HT）信号调节出生后瓣膜的组织生物力学，但对它们在胚胎瓣膜的生物力学重塑中的作用知之甚少。在这项研究中，我们证明外源性TGFβ3增加了AV垫的生物力学刚度和残余应力，但矛盾的是减少了基质压实。然后，我们发现TGFβ3诱导垫间充质中的收缩基因表达（RhoA，aSMA）和细胞外基质表达（col 1 α2），同时刺激增殖增加两倍。由于收缩表型升高，局部致密化增加，但由于增殖和ECM合成，整体致密化似乎减少。通过SB 431542阻断TGFβ I型受体可抑制TGFβ3的作用。我们接下来表明，外源性5-HT本身不影响垫刚度，但与TGFβ3共处理协同增加垫刚度。5-HT可促进TGFβ3基因表达，并呈剂量依赖性增强TGFβ3诱导的基因表达。阻断5-HT 2b受体，而不是5-HT 2a受体或5-羟色胺转运蛋白（SERT），导致TGFβ3诱导的机械强化完全停止。最后，在卵中全身给予5-HT诱导了垫重塑相关的缺陷，包括变薄/闭锁的AV瓣膜、室间隔缺损和流出道旋转缺损。卵内升高的5-HT导致重塑基因表达升高和TGFβ信号传导活性增加，支持我们的离体研究结果。总的来说，这些结果突出了TGFβ/5-HT信号传导作为在发育期间控制AV垫的生物力学重塑的有效机制。
Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of AV cushions during development.
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影响因子：
2.5
作者：
Azhar, Mohamad;Brown, Kristen;Gard, Connie;Chen, Hwudaurw;Rajan, Sudarsan;Elliott, David A.;Stevens, Mark V.;Camenisch, Todd D.;Conway, Simon J.;Doetschman, Thomas
通讯作者：
Doetschman, Thomas
影响因子：
2.5
作者：
Azhar, Mohamad;Runyan, Raymond B.;Gard, Connie;Sanford, L. Philip;Miller, Marian L.;Andringa, Anastasia;Pawlowski, Sharon;Rajan, Sudarsan;Doetschman, Thomas
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Doetschman, Thomas
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影响因子：
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作者：
Gustafsson, BI;Tommerås, K;Waldum, H
通讯作者：
Waldum, H
影响因子：
2.7
作者：
Boyer, AS;Ayerinskas, II;Runyan, RB
通讯作者：
Runyan, RB