Luttun Aernout, Tjwa Marc, Moons Lieve, Wu Yan, Angelillo-Scherrer Anne, Liao Fang, Nagy Janice A, Hooper Andrea, Priller Josef, De Klerck Bert, Compernolle Veerle, Daci Evis, Bohlen Peter, Dewerchin Mieke, Herbert Jean-Marc, Fava Roy, Matthys Patrick, Carmeliet Geert, Collen Désiré, Dvorak Harold F, Hicklin Daniel J, Carmeliet Peter
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium.
Nat Med. 2002 Aug;8(8):831-40. doi: 10.1038/nm731. Epub 2002 Jul 1.
The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
胎盘生长因子（PlGF）及其受体Flt1在血管生成中的治疗潜力尚未得到充分了解。在此，我们报告PlGF刺激缺血性心脏和肢体的血管生成及侧支生长，其效率至少与血管内皮生长因子（VEGF）相当。一种针对Flt1的抗体可抑制肿瘤和缺血视网膜中的新血管形成，以及自身免疫性关节炎中的血管生成和炎症性关节破坏。抗Flt1还可减少动脉粥样硬化斑块的生长和易损性，但动脉粥样硬化保护作用并非归因于斑块新血管形成的减少。抑制VEGF受体Flk1对关节炎或动脉粥样硬化没有影响，这表明仅抑制Flk1驱动的血管生成不足以阻止疾病进展。抗Flt1的抗炎作用归因于骨髓来源的髓系祖细胞向外周血中的动员减少；炎症组织中表达Flt1的白细胞浸润受损；以及髓系细胞的活化缺陷。因此，PlGF和Flt1构成了血管生成和炎症治疗调节的潜在候选物。
