Placenta growth factor is not required for exercise-induced angiogenesis

Abstract

Angiogenesis is a tightly regulated process, both during development and adult life. Animal models with mutations in the genes coding for placental growth factor (PlGF), a member of vascular endothelial growth factor (VEGF) family, or the tyrosine kinase domain of the PlGF receptor (Flt-1) have revealed differences between normal physiological angiogenesis and pathological angiogenesis associated with conditions such as tumor growth, arthritis and atherosclerosis. In the present paper, we investigated the potential role of PlGF in regulating physiological angiogenesis by analyzing vascular changes in heart and skeletal muscles of wild-type and Plgf-/- mice following prolonged and sustained physical training. Sedentary Plgf-/- mice showed a reduced capillary density in both heart and skeletal muscles as compared to wild-type mice (P < 0.05). However, after a 6-week training period, heart/body weight ratio, citrate synthase activity, vessel density and capillary/myocyte ratio were significantly increased in both wild-type and Plgf-/- mice (all P < 0.05). At the same time intercapillary distance was significantly reduced. Finally, acute exercise was not associated with any change in PlGF protein level in the skeletal muscle. Our results demonstrate that PlGF is not necessary for exercise-training-induced angiogenesis. We thus suggest that the role of PlGF is confined to the selective regulation of angiogenesis only under pathological conditions.

Partial persistence of exercise-induced myocardial angiogenesis following 4-week detraining in the rat

“…Altogether, these stimuli are likely to be the initiator events, directly or indirectly triggering the upregulation of a number of growth factors and of their cognate receptors on the target cells. Vascular endothelial growth factor (VEGF), and VEGF receptor 2 (KDR/Flk1) appear to be suYcient for the complete exercise-induced angiogenic response (Conway et al 2001;Gigante et al 2004;Bloor 2005). VEGF also upregulates the expression of matrix metalloproteinases, required for matrix remodeling and penetration of newly formed vessels Fig.…”

Angiogenesis during exercise and training

“…Interestingly when VEGF was injected locally into skeletal muscle and combined with exercise there was induced angiogenesis at that specific site. In another study involving placental growth factor (PlGF), a member of the VEGF family, the results indicate that PlGF is not necessary for exercise-training induced angiogenesis [71]. After exercise training vessel density and capillary/myocyte ratios were increased in both the wild-type and null mutation mice for PlGF.…”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…PlGF-deficient mice exhibit normal development, viability, and health, indicating that endogenous PlGF is dispensable for vascular development and homeostasis in the adult (Carmeliet et al 2001). PlGF is also not required for exercise-induced angiogenesis in the heart or skeletal muscle (Gigante et al 2004). This redundancy in health is further illustrated by the fact that an sFLT1 trap that neutralizes VEGF, VEGF-B, and PlGF induces a similar phenotype as an anti-VEGF antibody in healthy animals (Malik et al 2006).…”

“…A possible implication of these findings is that PlGF blockade might inhibit disease processes more selectively than physiological homeostasis and thus evoke fewer side effects. We summarize below the findings on PlGF's (Foidart et al 2009;Furuya et al 2011) Heart PlGF-induced revascularization of ischemic myocardium and vessel enlargement in remote myocardium preserve cardiac performance following infarction (Luttun et al 2002;Kolakowski et al 2006;Roncal et al 2008) Knockout: impaired angiogenesis and inflammation in infarct border (Carmeliet et al 2001) Knockout: Normal exercise induces angiogenesis (Gigante et al 2004) Skeletal muscle PlGF protein or gene delivery: enhances angiogenesis, collateral growth, and blood flow in ischemic limb (Luttun et al 2002;Pipp et al 2003;Babiak et al 2004); restores microcirculation in aged dystrophic muscle (Gargioli et al 2008) Knockout: impaired collateral growth in ischemic limb (Carmeliet et al 2001;Scholz et al 2003;Gigante et al 2006) Knockout: normal exercise-induced angiogenesis (Gigante et al 2004) Eye PlGF prevents vessel obliteration in hyperoxia without including neovascularization (Shih et al 2003) Local ocular PlGF protein or gene transfer causes hematoretinal barrier breakdown and edema (Miyamoto et al 2007;Kowalczuk et al 2011) Knockout or aPlGF: impaired choroidal neovascularization (Carmeliet et al 2001;Rakic et al 2003;Van de Veire et al 2010) Knockout or aPlGF does not impair retinal vascularization during development (Carmeliet et al 2001;Feeney et al 2003 (Carmeliet et al 2001;Scholz et al 2003;Gigante et al 2006) (Eriksson et al 2002;Xu et al 2006;Schomber et al 2007;Tarallo et al 2010) PlGF educates CD34 þ progenitors to proangiogenic CD11b þ myelomonocytes in breast cancer (Laurent et al 2011...…”