Pathomechanism of cerebral small vessel induced by TGFβ1 signalling

CARASIL是由丝氨酸蛋白酶HTRA1突变引起的，该酶调节转化生长因子-β(转化生长因子-β1)信号。CARASIL的病理特征是动脉硬化，内膜增厚，胶原纤维致密，血管平滑肌细胞丢失，脑小动脉中膜透明变性，类似于非遗传性脑小血管疾病。尽管转化生长因子-β1在维持正常血管壁结构中起着关键作用，但转化生长因子-β在动脉粥样硬化发展中的作用尚不清楚。为了阐明转化生长因子-β1在高血压脑和肾脏中的作用，我们在切除一侧肾脏和超负荷脱氧皮质酮(DOCA)和盐的大鼠中检测了转化生长因子-β1。大鼠一侧肾切除后，分别给予DOCA和1%氯化钠(DOCA-SALT)3周或4周。尾套法每周测量一次大鼠的收缩压(SBP)和心率(HR)。经腹股沟动脉插管侵入性测量平均动脉压(MAP)和心率后，取肾、主动脉、脑动脉和脑动脉。用双抗体夹心法和免疫印迹法检测各脏器组织中转化生长因子-β1的含量，结果显示，DOCA-盐组大鼠的SBP和MAP在发病过程中显著升高。3周后肾组织由0.06±0.005 ng/mg增至0.16±0.012 ng/mg，主动脉由0.59±0.07 ng/mg增至2.64±0.45 ng/mg。而转化生长因子-β1在3周后无明显变化，从0.019±0.004 ng/mg增加到0.022±0.003 ng/mg，而颈动脉和脑中的转化生长因子-β1在4周后显著升高，肾脏和主动脉中转化生长因子-β1的升高先于颈动脉和脑中转化生长因子-β1的升高。

CARASIL is caused by the mutation n the serine protease HTRA1, which regulates transforming growth factor-β (TGF-beta 1) signaling. The pathological feature of CARASIL is arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration of the tunica media in cerebral small arteries, which resembles nonhereditary cerebral small-vessel disease. While TGF-beta 1 plays a key role in the maintenance of normal blood vessel wall structure, the contribution of TGF-beta to the development of atherosclerosis is obscure. We examined TGF-beta 1 in rat removing unilateral kidney and overloading deoxycorticosterone（DOCA）and salt to clarify a role of TGF-beta 1 in the hypertensive brain and kidney. After unilateral kidney was removed, DOCA and 1% NaCl were administrated to a rat for 3 or4 weeks（DOCA-salt）. Systolic blood pressure (SBP) and heart rates (HR) in the rat were measured once a week by tail cuff method. After measuring mean arterial blood pressure (MAP) and HR by a cannula from inguinal artery invasively, kidney, aorta, cerebral artery and brain were removed. TGF -beta 1 in each organ was measured by ELISA and western blotting.SBP and MAP in the rat with DOCA-salt significantly increased during the course. TGF bera1 increased from 0.06 ± 0.005 ng/mg to 0.16 ± 0.012 ng/mg in the kidney, from 0.59 ± 0.07 ng/mg to 2.64 ± 0.45 ng/mg in the aorta after 3 weeks. While TGF bera1 did not change significantly from 0.019 ± 0.004 ng/mg to 0.022 ± 0.003 ng/mg after 3 weeks, but it increased significantly after 4 weeks in the cervical artery and the brain.The increase of the TGF bera1 in the kidney and the aorta precedes the increase of the TGF bera1 in the cervical artery and the brain.