我們這一系列的研究發現，化膿性肉芽瘤基於其在臨床上的特徵及我們的實驗結果，適合作為研究發炎性血管新生的人類疾病模式。第一部份的研究主題在探討化膿性肉芽瘤的成因，實驗發現化膿性肉芽瘤之中的血管新生相關促進因子，例如VEGF、bFGF、Ang-2、ephrinB2 及EphB4都比一般牙齦發炎及健康牙齦多。相對的血管靜止蛋白則表現較少。這表示化膿性肉芽瘤中的血管新生促進因子及抑制因子的確已經失去平衡。在第二部份的實驗中我們發現懷孕時期人類肉芽瘤的內皮細胞明顯較多於產後。而且，肉芽瘤中的VEGF與bFGF表現量的差異正好與它們的血管數量相呼應。在老鼠實驗中，動情素及動情素加黃體素治療能增加肉芽瘤的體積及重量。免疫轉漬的研究也證明在動情素治療及動情素加黃體素治療後的小鼠空氣囊肉芽瘤有較多的內皮細胞。而且利用ELISA方法可見荷爾蒙處理組的VEGF及bFGF的表現量較高。除此之外，黃體激素可以加強LPS刺激U937細胞生成VEGF。懷孕期女性類固醇荷爾蒙也可以降低U937細胞由於TNF-α所引起的細胞凋亡。綜合以上結果顯示，血管生成因子的過度表現可能是化膿性肉芽瘤的直接病因。而女性荷爾蒙可以讓血管生成因子的表現量超越閥值，保護活化巨噬細胞免於凋亡延長發炎性血管新生的效果，最後導致牙齦炎演變成肉芽瘤。
接著，我們探討化膿性肉芽瘤在生產完之後如何消退的機制。妊娠肉芽瘤中TNF-α的含量在分娩後顯著的增加。隨著TNF-α的濃度的增加，內皮細胞中Ang-2的轉錄也隨之上升。另外，在正常牙齦組織與分娩後妊娠肉芽瘤中VEGF的含量皆顯著少於懷孕時期的肉芽瘤。雖然分娩後的肉芽瘤Ang-2的含量仍然高於正常牙齦組織，但比懷孕時期的妊娠肉芽瘤少。體外纖維素凝膠分析中，Ang-2並沒有明顯的抑制新的微小管（microvessel）生成。而且Ang-2 (200 ng/mL)並不會造成細胞凋亡。所以Ang-2似乎不是妊娠肉芽瘤產後退化決定因素。相對的，培養液沒有添加VEGF時微小管發生細胞凋亡的情形較嚴重。因此我們推測產後的妊娠肉芽瘤因為缺乏VEGF或bFGF導致新生的血管發生細胞凋亡，而使肉芽瘤退化。
最後我們發現化膿性肉芽瘤中ephrinB2主要表現在巨噬細胞，而EphB4則表現在小靜脈。當ephrinB2刺激表現EphB4的內皮細胞後，在cDNA microarray分析下。至少有十三種基因表現受到影響。但是RT-PCR証實在內皮細胞內，只有syntenin及syndecan-1會隨著ephrinB2處理的時間及劑量而改變。而且ephrinB2會抑制FGF誘發臍動脈內皮細胞的增生及趨化作用。其中抑制的機制，可能是ephrinB2促進syndecan-1的表現，而過多的syndecan-1 ectodomain經過脫落(shedding)與FGFR競爭bFGF所導致的結果。但是在發炎時候大量增加的heparanase，可以將syndecan-1 ectodomain上的poorly sulfated heparan sulfate chain切除，這種改變特性的syndecan-1反而會促進FGFR的訊息傳導。這樣相反的反應或許可以用來解釋兩個重要的生理現象：在平常沒有發炎的時候，動脈(ephrinB2+)與靜脈(EphB4+)內皮細胞交接之處靠著抑制性的syndecan-1讓細胞對血管刺激因子反應遲鈍而保持恒定。但是當發炎時，heparanase表現增加將抑制性的syndecan-1轉變成促進性的分子，反而加強bFGF的訊息傳導。所以發炎時的新生血管大部分源自巨噬細胞(ephrinB2+)從小靜脈(EphB4+)穿越(diapedesis)的位置。

We conclude that pyogenic granuloma, based on its clinical characteristics and the results presented in this study, is an excellent model for the investigation of inflammatory angiogenesis. In the first part of our study, we found that levels of angiogenesis enhancers, such as VEGF, bFGF, Ang-2, ephrinB2, and EphB4 in pyogenic granuloma were significantly higher than those in regular gingivitis and normal gingiva. However, the expression of angiostatin in pyogenic granuloma was relatively less than that of the other groups. This indicated that angiogenesis enhancers and inhibitors were out of balance in pyogenic granuloma. In the second part of our study, we found that there were significantly more endothelial cells in pyogenic granuloma during pregnancy than after parturition. The angiogenesis phenotypes corresponded to the detected amount of VEGF and bFGF. In both human and animal studies, immunoassays detected significantly greater amounts of VEGF and bFGF and less TNF-a in hormones treated than in the control group, while TUNEL assay revealed fewer apoptotic cells in groups with pregnancy-levels of hormones. In vitro, progesterone enhanced the expression of VEGF in LPS-treated U937 cells. Both estrogen and progesterone reduced the apoptosis of U937 cells triggered by exogenous TNF-a. Female steroid hormones may have dual effects on the pathogenesis of pyogenic granuloma during pregnancy. They may not only enhance the expression of angiogenic factors in inflamed tissue, but may also decrease the apoptosis of granuloma cells to extend the angiogenic effect. A significantly greater amount of TNF-a was detected in pyogenic granuloma after parturition. The transcription of Ang-2 was upregulated by TNF-a in endothelial cells in vitro. Western blot analysis demonstrated that the level of VEGF in pyogenic granulomas was significantly less after parturition than during pregnancy. The Ang-2 level in pyogenic granuloma after parturition was significantly higher than in normal gingiva, but less than in granuloma during pregnancy. In an in vitro fibrin gel assay, Ang-2 up to 200 ng/mL did not cause more apoptosis compared with the control group. Ang-2 seemed not to play a determinant role in the regression of pyogenic granuloma. Nevertheless, two groups without added VEGF significantly more microvessel regression and apoptosis. We therefore speculated that the absence of angiogenic factors (e.g., VEGF, bFGF) lead to the regression of pyogenic granuloma after parturition. In the last part of our study, we found that ephrinB2 was predominantly expressed in macrophage-like cells while EphB4 was expressed in small venules. Since macrophages usually transmigrate through post-capillary venules when the latter are inflamed, we were very interested in exploring the downstream effects of EphB4 after it bound to ephrinB2. By using cDNA microarray technique followed by RT-PCR confirmation, we found that syntenin and syndecan-1 were up-regulated in EphB4-positive (EphB4+) endothelial cells dose- and time-dependently after stimulation with pre-clustered ephrinB2. In vitro, ephrinB2 suppressed the angiogenic effects of bFGF on EphB4+ endothelial cells, partially because of the competition between syndecan-1 and FGFR for bFGF. However, heparanase, an enzyme that is up-regulated under inflammatory condition, converts the inhibitory effect of ephrinB2 on EphB4+ endothelial cells to an activating effect. Syndecan-1 modified by heparanase is very plausible for the conversion. The results of our study may contribute to the understanding of two important physiological phenomena. Without inflammation, the interface between arterial and venous endothelial cells remains quiescent and homeostatic. When inflamed, new vessels arise overwhelmingly from the venous side of the circulation, where the ephrinB2+ macrophages transmigrate through EphB4+ endothelium. Syndecan-1 may play a dual role in these two different situations of vascular physiology.

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