University of Heidelberg, Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany.
FASEB J. 2011 Oct;25(10):3613-21. doi: 10.1096/fj.11-185975. Epub 2011 Jun 17.
An increase in circumferential wall tension (CWT) is an important determinant of vascular remodeling during hypertension or arteriosclerosis but also arteriogenesis. Although pivotal for such processes, the effect of this biomechanical force on venous remodeling has not yet been delineated. To this end, we raised the filling pressure in veins of the mouse auricle, which led to a 2.5-fold enlargement of these blood vessels within 4 d along with an increase in smooth muscle cell proliferation, matrix metalloproteinase 2 (MMP-2) expression and gelatinase activity. These changes were likewise observed in tissue samples of human varicose veins. Topical treatment of the auricles with a decoy oligonucleotide-neutralizing activator protein 1 (AP-1) inhibited these effects. Likewise, proliferation, MMP-2 expression, and gelatinase activity in both native and cultured venous smooth muscle cells exposed to enhanced stretch was decreased by up to 80% through inhibiting AP-1. In contrast, mutant control oligonucleotides had no effect on smooth muscle cell activation. These findings indicate that an increase in venous filling pressure and thus CWT is sufficient to activate AP-1, which, in turn, triggers varicose remodeling through fuelling MMP-2 activity and smooth muscle cell hyperplasia in the venous vessel wall.
环壁张力（CWT）的增加是高血压或动脉粥样硬化以及动脉生成过程中血管重塑的一个重要决定因素。尽管这种生物力学力对这些过程至关重要，但它对静脉重塑的影响尚未确定。为此，我们提高了小鼠耳廓静脉的充盈压，这导致这些血管在 4 天内扩大了 2.5 倍，同时平滑肌细胞增殖、基质金属蛋白酶 2（MMP-2）表达和明胶酶活性增加。在人类静脉曲张的组织样本中也观察到了这些变化。用诱饵寡核苷酸中和激活蛋白 1（AP-1）局部处理耳廓可抑制这些作用。同样，通过抑制 AP-1，暴露于增强的拉伸下的天然和培养的静脉平滑肌细胞的增殖、MMP-2 表达和明胶酶活性也分别降低了 80%。相比之下，突变体对照寡核苷酸对平滑肌细胞的激活没有影响。这些发现表明，静脉充盈压增加，从而 CWT 增加足以激活 AP-1，AP-1 转而通过激活 MMP-2 活性和静脉血管壁中平滑肌细胞的增生引发静脉曲张重塑。
