Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taiji M, Noguchi H, Matsumoto K, Nakamura T, Higaki J, Ogihara T
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Circulation. 1999 Nov 9;100(19 Suppl):II301-8. doi: 10.1161/circ.100.suppl_2.Ii-301.
Although hepatocyte growth factor (HGF), a novel angiogenic growth factor, plays an important role in angiogenesis, regulation of local HGF production under hypoxia has not yet been clarified in vascular smooth muscle cells (VSMC) and endothelial cells (EC). Thus, we have studied the role of HGF in hypoxia-induced endothelial injury and the regulation of local vascular HGF expression in response to hypoxia.
HGF attenuated hypoxia-induced endothelial cell death. Importantly, hypoxic treatment of EC resulted in a significant decrease in local HGF production according to the severity of hypoxia and increased VEGF. Similarly, hypoxia significantly decreased in mRNA and protein of HGF and increased VEGF production in VSMC. In organ culture system, local HGF production was also significantly decreased by hypoxia (P<0.01). Downregulation of HGF by hypoxia is due to a significant decrease in cAMP, as hypoxic treatment decreased cAMP, a stimulator of HGF. Although active TGF-beta, a suppressor of HGF, was increased at 72 hours after hypoxic treatment, treatment of anti-TGF-beta antibody did not attenuate decreased HGF production. Finally, rHGF was intra-arterially administered into unilateral hind limb ischemia rabbits, to evaluate in vivo angiogenic activity. Of importance, a single intra-arterial administration of rHGF reduced severe necrosis due to ischemia in rabbit muscle, accompanied by a significant increase in angiographic score (P<0.01).
Overall, these data demonstrated that hypoxic treatment of vascular cells significantly downregulated HGF production due to decreased cAMP, suggesting their potential roles in the pathophysiology of ischemic diseases. Moreover, administration of rHGF induced therapeutic angiogenesis, accompanied by improvement of necrotic changes in the ischemic hind limb model, as cytokine supplement therapy for peripheral arterial disease.
尽管肝细胞生长因子（HGF）作为一种新型血管生成生长因子在血管生成中发挥重要作用，但血管平滑肌细胞（VSMC）和内皮细胞（EC）在缺氧条件下局部HGF产生的调控机制尚未阐明。因此，我们研究了HGF在缺氧诱导的内皮损伤中的作用以及血管局部HGF表达对缺氧的反应调控。
HGF减轻了缺氧诱导的内皮细胞死亡。重要的是，根据缺氧的严重程度，对EC进行缺氧处理导致局部HGF产生显著减少，而VEGF增加。同样，缺氧显著降低了VSMC中HGF的mRNA和蛋白水平，并增加了VEGF的产生。在器官培养系统中，缺氧也显著降低了局部HGF的产生（P<0.01）。缺氧导致HGF下调是由于cAMP显著减少，因为缺氧处理降低了作为HGF刺激物的cAMP。尽管活性转化生长因子-β（TGF-β）作为HGF的抑制剂在缺氧处理72小时后增加，但抗TGF-β抗体处理并未减轻HGF产生的减少。最后，将重组人HGF（rHGF）动脉内注射到单侧后肢缺血兔体内，以评估体内血管生成活性。重要的是，单次动脉内注射rHGF减少了兔肌肉因缺血导致的严重坏死，同时血管造影评分显著增加（P<0.01）。
总体而言，这些数据表明，对血管细胞进行缺氧处理会因cAMP减少而显著下调HGF的产生，提示它们在缺血性疾病病理生理学中的潜在作用。此外，rHGF给药诱导了治疗性血管生成，并伴随着缺血后肢模型坏死变化的改善，可以作为外周动脉疾病的细胞因子补充疗法。
