Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway
Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway
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DOI：
10.1161/01.res.0000109413.57726.91
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发表时间：
2004-01-09
影响因子：
20.1
通讯作者：
Fernandez-Patron, C
中科院分区：
文献类型：
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作者：
Hao, L;Du, M;Fernandez-Patron, C
基质金属蛋白酶依赖的肝素结合的表皮生长因子(HB-EGF)的脱落和EGF受体(EGFR)的激活是多种G蛋白偶联受体(GPCRs)生长效应的一种独特的信号机制。在这些GPCRs中，有肾上腺素受体和血管紧张素受体，它们通过血管收缩和生长作用参与高血压的发病。聚焦于α(1b)-肾上腺素能受体，我们认为，依赖于基质金属蛋白酶的EGFR的激活促进了血管收缩和生长。我们发现大鼠肠系膜动脉中的主要HB-EGF脱落酶和α(1b)肾上腺素受体、血管紧张素受体和高血压刺激的MMP-7活性。肾上腺素受体刺激动脉中的EGFR自动磷酸化，这种反式激活被基质金属蛋白酶-7抑制剂GM6001和基质金属蛋白酶-7特异性抗体所拮抗。在离体微灌流动脉中，用EGFR(AG1478和PD153035)、HB-EGF(CRM197和中和抗体)或MMPs(多西环素)抑制剂阻断EGFR反式激活可抑制肾上腺素能血管收缩。在自发性高血压大鼠，用多西环素(19.2 mg/d，从第7周到第12周)抑制MMPs，可降低收缩压，减少HB-EGF在肠系膜动脉的脱落。这些发现提示了一种以前未知的血管调节机制，即某些GPCRs的激动剂(如肾上腺素受体和血管紧张素受体)激活MMPs(如MMP-7)，使其释放EGFR配体(如HB-EGF)，然后再激活EGFR，从而促进血管收缩和生长。由于这一机制是由高血压患者中典型的过度表达的激动剂触发的，因此它的阻断可能具有同时抑制高血压疾病中病理性血管收缩和生长的治疗潜力。
Matrix metalloproteinase (MMP)-dependent shedding of heparin-binding epidermal growth factor (HB-EGF) and subsequent activation of the EGF receptor (EGFR) in the cardiovasculature is emerging as a unique mechanism signaling growth effects of diverse G protein-coupled receptors (GPCRs). Among these GPCRs are adrenoceptors and angiotensin receptors that contribute to the pathogenesis of hypertension through their vasoconstrictive and growth effects. Focusing on alpha(1b)-adrenoceptors, we suggest here that MMP-dependent activation of the EGFR promotes vasoconstriction as well as growth. We identified MMP-7 as a major HB-EGF sheddase in rat mesenteric arteries and alpha(1b)-adrenoceptors, angiotensin receptors, and hypertension-stimulated MMP-7 activity. Adrenoceptors stimulated EGFR autophosphorylation in arteries, and this transactivation was opposed by the MMP-7 inhibitor GM6001 as well as MMP-7-specific antibodies. In isolated microperfused arteries, blockade of EGFR transactivation with inhibitors of the EGFR (AG1478 and PD153035), HB-EGF (CRM197 and neutralizing antibodies), or MMPs (doxycycline) inhibited adrenergic vasoconstriction. In spontaneously hypertensive rats but not in normotensive rats, the inhibition of MMPs with doxycycline (19.2 mg/d from week 7 until week 12) reduced systolic blood pressure and attenuated HB-EGF shedding in the mesenteric arteries. These findings suggest a previously unknown mechanism of vasoregulation whereby agonists of certain GPCRs (such as adrenoceptors and angiotensin receptors) activate MMPs (such as MMP-7) that shed EGFR ligands (such as HB-EGF), which then activate the EGFR, thereby promoting vasoconstriction as well as growth. Because this mechanism is triggered by agonists typically overexpressed in hypertension, its blockade may have therapeutic potential for simultaneously inhibiting pathological vasoconstriction and growth in hypertensive disorders.