Jesmin Subrina, Hattori Yuichi, Togashi Hiroko, Ueno Ken-ichi, Yoshioka Mitsuhiro, Sakuma Ichiro
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Mol Cell Biochem. 2005 Apr;272(1-2):63-73. doi: 10.1007/s11010-005-7635-3.
We examined the age-related changes in cardiac expression of angiogenic molecules during the development of cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHRSP) in comparison with those in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) was highly upregulated in SHRSP aged 20 weeks compared with the same age of WKY, but it was downregulated at 40 weeks. On the other hand, KDR, an angiogenic receptor of VEGF, and endothelial nitric oxide synthase, which is important in the VEGF-mediated angiogenic pathway, were markedly downregulated in SHRSP from 20 weeks of age. Such age-related changes in their expression levels seen in SHRSP were quite different from those in SHR. In both SHR and SHRSP, transforming growth factor-beta1 (TGF-beta1) expression was increased with age, although SHRSP showed more marked upregulation. Cardiac remodeling in SHRSP was characterized by decreased coronary capillary density, cardiomyocyte hypertrophy, and cardiac fibrosis. We conclude that, in addition to overexpression of TGF-beta1, which appears to play a pivotal role in promoting cardiac hypertrophy and fibrosis, a defect of the VEGF-KDR system could result in impaired physiologic coronary angiogenesis in SHRSP, contributing to cardiac deteroration associated with myocardial ischemia in this malignant hypertensive model.
我们研究了易中风自发性高血压大鼠（SHRSP）心脏重塑过程中血管生成分子心脏表达的年龄相关变化，并与Wistar-Kyoto大鼠（WKY）和自发性高血压大鼠（SHR）进行了比较。与同龄的WKY相比，20周龄的SHRSP中血管内皮生长因子（VEGF）高度上调，但在40周时下调。另一方面，VEGF的血管生成受体KDR以及在VEGF介导的血管生成途径中起重要作用的内皮型一氧化氮合酶在20周龄的SHRSP中显著下调。SHRSP中观察到的这些表达水平的年龄相关变化与SHR中的变化有很大不同。在SHR和SHRSP中，转化生长因子-β1（TGF-β1）的表达均随年龄增加，尽管SHRSP的上调更为明显。SHRSP的心脏重塑表现为冠状动脉毛细血管密度降低、心肌细胞肥大和心脏纤维化。我们得出结论，除了TGF-β1的过表达似乎在促进心脏肥大和纤维化中起关键作用外，VEGF-KDR系统的缺陷可能导致SHRSP中生理性冠状动脉血管生成受损，促成这种恶性高血压模型中与心肌缺血相关的心脏恶化。
