STRESS-ACTIVATED SIGNALING IN VASCULAR SMOOTH MUSCLE CELLS DERIVED FROM PATIENTS WITH MOYAMOYA DISEASE

烟雾病是一种进行性脑血管闭塞性疾病，主要影响儿童。主要的血管病变是狭窄或闭塞，内膜纤维细胞增厚。原因尚不清楚。我们先前发现烟雾病患者培养的平滑肌细胞通过激活环氧合酶-2响应于白细胞介素-1产生过量的前列腺素E2，导致血管通透性增加。在这里，我们证明烟雾SMC高度产生大量的血管内皮生长因子，一个强大的血管通透性因子，以及血管生成因子，白细胞介素-1的刺激。烟雾平滑肌细胞中p38有丝分裂原激活激酶的磷酸化上调，随后环氧合酶-2的激活导致白细胞介素-1过量释放血管内皮生长因子和前列腺素E2。烟雾病平滑肌细胞对炎症刺激的反应性更高，这是烟雾病平滑肌细胞的一个显著特征，通过p38丝裂原活化激酶磷酸化机制紊乱引起内膜增厚和血管生成增强。

Moyamoya disease is a progressive cerebrovascular occlusive disease affecting primarily children. The main vascular leions are stenosis or occlusion with fibrocellular thickening of the intima. The cause remains unknown. We previouly found that cultured smooth muscle cells from moyamoya patients produce excess amounts of prostaglandin E2 in response to interleukin-1 via activation of cyclooxygenase-2, leading to increase in vascular permeability. Here, we demonstrate that moyamoya SMCs highly produce large amounts of vascular endothelial growth factor, a powerful vascular permeability factor as well as an angiogenic factor, by interleukin-1 stimulation. Up-regulated phosphorylation of p38 mitogen-activated kinase followed by activation of cyclooxygenase-2 in moyamoya smooth muscle cells contributed to the excess release of vascular endothelial growth factor and prostaglandin E2 by interleukin-1. Higher responsibility to inflammatory stimuli is a distinct feature of moyamoya smooth muscle cells, causing intimal thickening as well as an enhanced angiogenesis via disordered p38 mitogen-activated kinase phosphorylation machinery.