Flamant Martin, Placier Sandrine, Dubroca Caroline, Esposito Bruno, Lopes Izolina, Chatziantoniou Christos, Tedgui Alain, Dussaule Jean-Claude, Lehoux Stéphanie
Institut National de la Santé et de la Recherche Médicale (INSERM) U689, Centre de Recherche Cardiovasculaire Inserm Lariboisière, Paris, France.
Hypertension. 2007 Jul;50(1):212-8. doi: 10.1161/HYPERTENSIONAHA.107.089631. Epub 2007 May 21.
Hypertension is associated with vascular remodeling characterized by rearrangement of extracellular matrix proteins. To evaluate how matrix metalloproteinase (MMP)-9 contributes to the progression of hypertensive vascular disease in vivo, wild-type (wt) or MMP-9(-/-) mice were treated with angiotensin II (Ang II; 1 microg/kg per minute, by minipump) plus a 5% NaCl diet during 10 days. Baseline blood pressure was equivalent in wt and knockout mice, but Ang II treatment increased systolic blood pressure to a greater extent (P<0.05) in MMP-9(-/-) mice (94+/-6 to 134+/-6 mm Hg; P<0.001) than in wt animals (93+/-4 to 114+/-6 mm Hg; P<0.01). In wt mice, Ang II treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981+/-19 microm (P<0.01 versus sham; 891+/-10 microm). In contrast, in MMP-9(-/-) mice, carotid artery compliance was actually reduced after Ang II (P<0.05), and maximal diameter only reached 878+/-13 microm. Ang II treatment induced MMP-2 and increased carotid media thickness equally in both phenotypes. However, MMP-9 induction and in situ gelatinase activity were only enhanced in Ang II-treated wt mice, and vessels from these mice also produced more collagen I breakdown products than their MMP-9(-/-) counterparts (P<0.05). Inversely, staining for collagen IV was particularly enhanced in vessels from MMP-9(-/-) mice treated with Ang II. These results demonstrate the following: (1) the onset of Ang II-induced hypertension is accompanied by increased MMP-9 activity in conductance vessels; (2) absence of MMP-9 activity results in vessel stiffness and increased pulse pressure; and (3) MMP-9 activation is associated with a beneficial role early on in hypertension by preserving vessel compliance and alleviating blood pressure increase.
高血压与以细胞外基质蛋白重排为特征的血管重塑相关。为了评估基质金属蛋白酶（MMP）-9在体内如何促进高血压血管疾病的进展，野生型（wt）或MMP-9基因敲除（-/-）小鼠在10天内接受血管紧张素II（Ang II；1微克/千克每分钟，通过微型泵）加5%氯化钠饮食治疗。wt小鼠和基因敲除小鼠的基线血压相当，但Ang II治疗使MMP-9（-/-）小鼠（94±6至134±6毫米汞柱；P<0.001）的收缩压升高幅度大于wt动物（93±4至114±6毫米汞柱；P<0.01）（P<0.05）。在wt小鼠中，Ang II治疗显著增加了颈动脉压力-直径关系，最大直径达到981±19微米（与假手术组相比P<0.01；891±10微米）。相反，在MMP-9（-/-）小鼠中，Ang II治疗后颈动脉顺应性实际上降低了（P<0.05），最大直径仅达到878±13微米。Ang II治疗在两种表型中均诱导MMP-2并同等程度增加颈动脉中层厚度。然而，MMP-9的诱导和原位明胶酶活性仅在Ang II治疗的wt小鼠中增强，并且这些小鼠的血管比其MMP-9（-/-）对应物产生更多的I型胶原降解产物（P<0.05）。相反，在用Ang II治疗的MMP-9（-/-）小鼠的血管中，IV型胶原染色特别增强。这些结果表明：（1）Ang II诱导的高血压发作伴随着传导血管中MMP-9活性增加；（2）MMP-9活性缺失导致血管僵硬和脉压增加；（3）MMP-9激活在高血压早期通过维持血管顺应性和减轻血压升高发挥有益作用。
