Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta.
Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta.
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发表时间：
1994-02
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通讯作者：
M. Botney;Lila Bahadori;Goldt
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作者：
M. Botney;Lila Bahadori;Goldt
活性外源性转化生长因子-β (TGF-β) 是细胞培养物中细胞外基质合成的有效调节剂，并刺激伤口和其他重塑组织中的基质合成。内源性 TGF-β 在组织重塑中的作用尚不清楚。原发性肺动脉高压患者肺动脉血管重塑的部分特征是免疫组织化学可检测到的原胶原异常沉积，从而识别活跃的重塑血管。我们使用活性基质合成的这一标记来开始定义 TGF-β 在主动重塑组织的复杂环境中的体内作用。使用异构体特异性抗 TGF-β 抗体进行免疫组织化学，以确定 TGF-β 是否存在于直径 20 至 500 微米的主动重塑高血压肺动脉中。在这些高血压肌性动脉的中膜和新内膜中观察到强烈的细胞相关 TGF-β3 免疫反应性。在大小相当的正常动脉中存在免疫染色，但强度较低。在正常血管中观察到 TGF-β 2 免疫反应性，在高血压血管中略有增加，其模式类似于 TGF-β 3 免疫反应性。外膜没有染色。正常血管和高血压血管中 TGF-β1 免疫染色都很弱或不存在。前胶原和 TGF-β 定位的比较表明，TGF-β 2 和 TGF-β 3 在前胶原合成的所有位点共定位。然而，在没有前胶原合成的血管或血管室中观察到了 TGF-β。对 TGF-β 2 和 TGF-β 3 表现出免疫反应性的正常血管中不存在原胶原免疫反应性。这些观察结果表明：a）体内 TGF-β 对原胶原合成的刺激比体外研究表明的更为复杂，b）TGF-β 2 或 TGF-β 3 而不是 TGF-β 1 在高血压肺血管重塑中具有潜在作用。
Active exogenous transforming growth factor-beta s (TGF-beta s) are potent modulators of extracellular matrix synthesis in cell culture and stimulate matrix synthesis in wounds and other remodeling tissues. The role of endogenous TGF-beta s in remodeling tissues is less well defined. Vascular remodeling in the pulmonary arteries of patients with primary pulmonary hypertension is characterized, in part, by abnormal deposition of immunohistochemically detectable procollagen, thereby identifying actively remodeling vessels. We used this marker of active matrix synthesis to begin defining the in vivo role of TGF-beta in the complex milieu of actively remodeling tissues. Immunohistochemistry using isoform-specific anti-TGF-beta antibodies was performed to determine whether TGF-beta was present in actively remodeling hypertensive pulmonary arteries 20 to 500 microns in diameter. Intense, cell-associated TGF-beta 3 immunoreactivity was observed in the media and neointima of these hypertensive muscular arteries. Immunostaining was present, but less intense, in normal arteries of comparable size. TGF-beta 2 immunoreactivity was observed in normal vessels and was increased slightly in hypertensive vessels, in a pattern resembling TGF-beta 3 immunoreactivity. No staining was associated with the adventitia. TGF-beta 1 immunostaining was either faint or absent in both normal and hypertensive vessels. Comparison of procollagen and TGF-beta localization demonstrated that TGF-beta 2 and TGF-beta 3 colocalized at all sites of procollagen synthesis. However, TGF-beta was observed in vessels, or vascular compartments, where there was no procollagen synthesis. Procollagen immunoreactivity was not present in normal vessels that showed immunoreactivity for TGF-beta 2 and TGF-beta 3. These observations suggest: a) the stimulation of procollagen synthesis by TGF-beta in vivo is more complex than suggested by in vitro studies and b) a potential role for TGF-beta 2 or TGF-beta 3, but not TGF-beta 1, in hypertensive pulmonary vascular remodeling.