Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling - Potential implications in atherosclerosis and lymphangioleiomyomatosis
Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling - Potential implications in atherosclerosis and lymphangioleiomyomatosis
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DOI：
10.1016/s0002-9440(10)63716-9
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发表时间：
2004-05-01
影响因子：
6
通讯作者：
Raines, EW
中科院分区：
文献类型：
--
作者：
Ferri, N;Carragher, NO;Raines, EW
血管和肺的阻塞性疾病的特征在于新的细胞外基质（ECM）组分的降解和合成。在诸如动脉粥样硬化和淋巴管平滑肌瘤病（LAM）的疾病中，ECM的调节重塑（两者均以平滑肌细胞（SMC）的过度积累为特征）被认为部分地由特定ECM组分的细胞表面受体控制。盘状结构域受体（DDR）1和2代表由纤维状胶原激活的酪氨酸激酶胶原受体家族。为了验证DDR可能参与SMC在体内ECM重塑的假设，我们通过逆转录-聚合酶链反应和免疫组化分析了DDR的表达，并证明与正常对照组相比，DDR 1和DDR 2在LAM结节中上调，并在动脉粥样硬化病变中表达。在体外，在聚合胶原凝胶上培养的人SMC中，逆转录病毒过量表达DDR 1或DDR2导致胶原表达减少，并在mRNA和蛋白水平诱导基质金属蛋白酶（MMP）1，但只有DDR2增强MMP 2活化。此外，DDR2过表达增加SMC介导的胶原和弹性蛋白降解。使用激光显微切割，我们将我们的研究扩展到LAM结节的SMC分析，我们观察到较高的MMP 1表达和MMP 2激活。总之，这些数据提供了证据DDR 1和DDR2在血管和肺阻塞性疾病中SMC介导的胶原蛋白周转调节中的潜在作用。
Obstructive diseases of blood vessels and the lung are characterized by degradation and synthesis of new extracellular matrix (ECM) components. Regulated remodeling of the ECM in diseases such as atherosclerosis and lymphangioleiomyomatosis (LAM), both characterized by excessive accumulation of smooth muscle cells (SMCs), is thought to be controlled in part by cell surface receptors for specific ECM components. Discoidin domain receptors (DDR) 1 and 2 represent a family of tyrosine kinase collagen receptors that are activated by fibrillar collagens. To test the hypothesis that DDR may be involved in ECM remodeling by SMCs in vivo, we analyzed DDR expression by reverse transcriptase-polymerase chain reaction and immunohistochemistry and demonstrate that both DDR1 and DDR2 are up-regulated in nodules of LAM as compared to normal controls, and are expressed in lesions of atherosclerosis. In vitro, retroviral overexpression of DDR1 or DDR2 in human SMCs cultured on polymerized collagen gels leads to a reduction of collagen expression and induces matrix metalloproteinase (MMP) 1 at both mRNA and protein levels, but only DDR2 enhances MMP2 activation. Moreover, DDR2 overexpression increases SMC-mediated collagen and elastin degradation in vitro. Using laser microdissection, we extend our studies to the analysis of SMCs from LAM nodules where we observe higher MMP1 expression and MMP2 activation. Taken together, these data provide evidence for the potential roles of DDR1 and DDR2 in the regulation of collagen turnover mediated by SMCs in obstructive diseases of blood vessels and the lung.