Couto Rafael A, Kulungowski Ann M, Chawla Aditya S, Fishman Steven J, Greene Arin K
Department of Plastic and Oral Surgery, Harvard Medical School, Boston, Massachusetts, USA.
Lymphat Res Biol. 2011;9(3):143-9. doi: 10.1089/lrb.2011.0008.
Lymphedema is the progressive distention of tissue due to lymphatic dysfunction. The affected area enlarges over time because of fibroadipose deposition, causing morbidity. Because increasing tissue mass requires neovascularization, we hypothesized that angiogenesis or vasculogenesis might be upregulated in lymphedema.
Lymphedematous tissue was collected prospectively from nine patients after resection: upper extremity (n = 1), lower extremity (n = 3), penis/scrotum (n = 5). Neovascularization was compared to normal tissue. Specimens were analyzed using immunohistochemistry for α-smooth muscle actin (pericyte marker), CD31 (microvascular density), CD31/Ki67 (proliferating endothelial cells), and CD34/CD133 (endothelial progenitor cells). Quantitative real-time PCR (qRT-PCR) was used to determine mRNA expression of progenitor cells (CD133) and factors that recruit them: vascular endothelial growth factor-A (VEGF-A), hypoxia-inducible factor 1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), and stromal-cell derived factor 1α (SDF-1α). Angiopoetin-1,-2 (ANG-1,-2), matrix metalloproteinase-2 (MMP-2), and VEGF receptors (VEGFR1,2) were quantified using qRT-PCR. There was no difference in microvascular density, pericytic density, or endothelial proliferation between lymphedematous and normal tissue (p = 0.1). Endothelial progenitor cells were not present in lymphedema or normal specimens (p < 0.01). VEGF-A (1.3-fold), HIF-1α (0.8-fold), SDF-1α (2.1-fold), VEGFR2 (0.09-fold), and CD133 (0.02-fold) expression were not elevated compared to normal tissue (p = 0.1). ANG-1 (5.6-fold), ANG-2 (2.5-fold), MMP-2 (3.9-fold), MMP-9 (33.4-fold), and VEGFR1 (12.8-fold) mRNA was increased in lymphedematous specimens compared to control (p < 0.05).
Lymphedematous tissue does not exhibit upregulation of angiogenesis or vasculogenesis. Neovascularization is unlikely to be involved in the pathogenesis of this disease.
淋巴水肿是由于淋巴功能障碍导致的组织进行性扩张。随着时间的推移，受影响区域会因纤维脂肪沉积而增大，从而引发病变。由于组织质量增加需要新血管形成，我们推测在淋巴水肿中血管生成或血管发生可能上调。
前瞻性收集了9例患者切除术后的淋巴水肿组织：上肢（1例）、下肢（3例）、阴茎/阴囊（5例）。将新血管形成与正常组织进行比较。使用免疫组织化学分析标本中的α-平滑肌肌动蛋白（周细胞标志物）、CD31（微血管密度）、CD31/Ki67（增殖内皮细胞）和CD34/CD133（内皮祖细胞）。采用定量实时聚合酶链反应（qRT-PCR）来确定祖细胞（CD133）及其募集因子的mRNA表达：血管内皮生长因子-A（VEGF-A）、缺氧诱导因子1α（HIF-1α）、基质金属蛋白酶-9（MMP-9）和基质细胞衍生因子1α（SDF-1α）。使用qRT-PCR对血管生成素-1、-2（ANG-1、-2）、基质金属蛋白酶-2（MMP-2）和VEGF受体（VEGFR1、2）进行定量。淋巴水肿组织与正常组织在微血管密度、周细胞密度或内皮细胞增殖方面无差异（p = 0.1）。淋巴水肿或正常标本中均不存在内皮祖细胞（p < 0.01）。与正常组织相比，VEGF-A（1.3倍）、HIF-1α（0.8倍）、SDF-1α（2.1倍）、VEGFR2（0.09倍）和CD133（0.02倍）的表达未升高（p = 0.1）。与对照组相比，淋巴水肿标本中ANG-1（5.6倍）、ANG-2（2.5倍）、MMP-2（3.9倍）、MMP-9（33.4倍）和VEGFR1（12.8倍）的mRNA增加（p < 0.05）。
淋巴水肿组织未表现出血管生成或血管发生的上调。新血管形成不太可能参与该疾病的发病机制。
