Capillary regression in vascular endothelial growth factor-deficient skeletal muscle

Abstract

Skeletal muscle angiogenesis is an important physiological adaptation to increased metabolic demand, possibly dependent on vascular endothelial growth factor (VEGF), the increased expression of which is a known early response to exercise. To test the hypothesis that VEGF is essential to muscle capillary maintenance, we evaluated the consequences of targeted skeletal muscle inhibition of VEGF expression in postnatal, cage-confined VEGF loxP(+/+) mice. To delete VEGF, cre recombinase expression was accomplished using direct intramuscular injection of a recombinant adeno-associated cre recombinase expressing viral vector. Four weeks postinfection, VEGF-inactivated regions revealed 64% decreases in capillary density and capillary-to-fiber ratio. Substantial apoptosis was also observed in VEGF-depleted regions. There was no evidence of rescue at 8 wk, with a persistent 67% reduction in capillary-to-fiber ratio and a 69% decrease in capillary density. These data implicate VEGF as an essential survival factor for muscle capillarity and also demonstrate insufficient VEGF-dependent signaling leads to apoptosis in mouse skeletal muscle.

O treinamento físico aeróbio inibe a sinalização apoptótica muscular esquelética mediada por VEGF-VEGR2 em ratos espontaneamente hipertensos

“…Considering the evidence, VEGF is considered the most important regulator of angiogenesis, chemotaxis and endothelial cell survival by preventing the activation of signaling pathways of apoptosis, consequently the capillary loss 8 . In fact, deletion or inhibition of VEGF in skeletal muscles of adult mice has shown adverse effects, particularly a significant reduction in capillary density with endothelial cell apoptosis 23 . It is known that the angiogenic response mediated by regular practice of aerobic physical exercise involves many mechanisms, such as increase of blood flow, triggering increase of shear stress and tension on the capillaries walls, hypoxia, activating the hypoxiainducible factor (HIF-1α), the renin-angiotensin system, among others, which are responsible for induction of vascular growth factors, especially the VEGF 24 .…”

“…The homogenate was centrifuged for 10 minutes at 4°C with 12,000rpm. The supernatant was transferred to 1.5 ml tubes and the protein concentration of the samples was analyzed in the Bradford method 23 . The samples were stored in freezer -80ºC until usage.…”

Linking brains and brawn: exercise and the evolution of human neurobiology

“…The relationship between VO 2,max and brain size across mammals is likely to be related to differences in VEGF expression in more athletic taxa [6], because VO 2,max is positively correlated with the volume of muscle capillary networks across mammals, driven by the need to deliver oxygen during APA [52]. Because skeletal muscle capillarity is regulated by VEGF [51,69], the increased volume of the capillary network found in mammals with high aerobic capacities may be due to evolutionarily altered VEGF signalling.…”

Regulation of myogenic stem cell behaviour by vessel cells: The "ménage à trois" of satellite cells, periendothelial cells and endothelial cells

“…[12][13][14][15][16] Chronic pathological conditions, such as Chronic Obstruction Pulmonary Disease (COPD) and diabetes, 17,18 induce capillary rarefaction suggesting that VEGF is also important in the maintenance of adult skeletal muscle microvasculature. Indeed, the study of Tang et al 19 have implicated VEGF as an essential survival factor for basal skeletal muscle capillarization. 20 Furthermore, the marked decrease of capillary-to-fibre ratio (-48%) and capillary density (-39%) in gastrocnemius of …”