Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells.
Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells.
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DOI：
10.1084/jem.193.9.1005
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发表时间：
2001-05-07
期刊：
影响因子：
--
通讯作者：
Rafii S
中科院分区：
文献类型：
--
作者：
Hattori K;Dias S;Heissig B;Hackett NR;Lyden D;Tateno M;Hicklin DJ;Zhu Z;Witte L;Crystal RG;Moore MA;Rafii S
血管生成因子酪氨酸激酶受体血管内皮生长因子（VEGF）和血管生成素-1 （Ang-1）不仅在内皮细胞中表达，而且在造血干细胞（hsc）亚群中表达。为了进一步确定VEGF和Ang-1在出生后造血和血管发生中的调节作用，通过向小鼠注射表达可溶性VEGF165、基质结合VEGF189或Ang-1的重组蛋白或腺病毒载体，提高了VEGF和Ang-1的血浆水平。VEGF165，而不是VEGF189，诱导造血干细胞和VEGF受体（VEGFR）2+循环内皮前体细胞（cep）的快速动员。相反，Ang-1诱导cep和hsc的延迟动员。Ang-1和VEGF165的持续联合升高与造血功能的诱导和骨髓细胞的增加有关，随后是毛细血管的增殖和窦腔的扩张。伴随着这种血管重塑，骨髓中造血活性的短暂耗竭，通过向脾脏动员和募集hsc和cep的增加来补偿，导致脾肿大。中和VEGFR2单克隆抗体完全抑制VEGF165，但不能抑制ang -1诱导的动员和脾肿大。这些数据表明，VEGF/VEGFR2和Ang-1/Tie-2信号通路的时间和区域激活对于hsc和cep的动员和募集至关重要，并可能在出生后血管生成和造血生理中发挥作用。
Tyrosine kinase receptors for angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) are expressed not only by endothelial cells but also by subsets of hematopoietic stem cells (HSCs). To further define their role in the regulation of postnatal hematopoiesis and vasculogenesis, VEGF and Ang-1 plasma levels were elevated by injecting recombinant protein or adenoviral vectors expressing soluble VEGF165, matrix-bound VEGF189, or Ang-1 into mice. VEGF165, but not VEGF189, induced a rapid mobilization of HSCs and VEGF receptor (VEGFR)2+ circulating endothelial precursor cells (CEPs). In contrast, Ang-1 induced delayed mobilization of CEPs and HSCs. Combined sustained elevation of Ang-1 and VEGF165 was associated with an induction of hematopoiesis and increased marrow cellularity followed by proliferation of capillaries and expansion of sinusoidal space. Concomitant to this vascular remodeling, there was a transient depletion of hematopoietic activity in the marrow, which was compensated by an increase in mobilization and recruitment of HSCs and CEPs to the spleen resulting in splenomegaly. Neutralizing monoclonal antibody to VEGFR2 completely inhibited VEGF165, but not Ang-1–induced mobilization and splenomegaly. These data suggest that temporal and regional activation of VEGF/VEGFR2 and Ang-1/Tie-2 signaling pathways are critical for mobilization and recruitment of HSCs and CEPs and may play a role in the physiology of postnatal angiogenesis and hematopoiesis.
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