Figure 2

Flt-1 is a decoy receptor for vascular endothelial growth factor (VEGF) pro-angiogenic signaling. (A) In the wild-type scenario, VEGF induces a pro-angiogenic signal by binding the Flt-1 or Flk-1 receptors [63]. Flt-1 has a higher binding affinity for VEGF but transmits a weaker angiogenic signal compared to Flk-1, which implies that Flt-1 acts a negative regulator of angiogenesis [63]. The soluble form of Flt-1 (sFlt-1) lacks the transmembrane and intracellular signaling domains of Flt-1 and only serves a regulatory role by sequestering VEGF [63]. (B) Flt-1 homozygous knockout (Flt-1^−/−) mice die in the early embryonic stage from endothelial cell overproduction and blood vessel disorganization, indicating that Flt-1 is a decoy regulator for endothelial growth/differentiation [64–66]. (C) Flk-1 homozygous knockout (Flk-1^−/−) mice die in the early embryonic stage from defects in the development of organized blood vessels, indicating that Flk-1 is a positive regulator for endothelial growth/differentiation [67]. (D) Developmental reduction of the Flt-1 receptor through haploinsufficiency of the Flt-1 gene (Flt-1^+/−) has been shown to increase capillary density in skeletal muscle, and this same phenomenon has been demonstrated in mdx mice (mdx:Flt-1^+/−) [79]. The mdx:Flt-1^+/− mice also showed improved histological and functional parameters normally associated with the Duchenne muscular dystrophy (DMD) pathology [68].