Premium
VEGF knockdown in muscle improves recovery of blood flow and arteriolargenesis after ischaemia
Author(s) -
Machado Maria J C,
Riu Federica,
Benest Andrew V,
Bates David O
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.721.1
Subject(s) - vascular endothelial growth factor , blood flow , skeletal muscle , isoflurane , genetically modified mouse , medicine , ischemia , endocrinology , chemistry , transgene , anesthesia , vegf receptors , biochemistry , gene
Vascular Endothelial Growth Factor (VEGF) signalling is essential for endothelial cell homeostasis and growth. It has thus been assumed that VEGF would be important during the revascularization process that occurs in ischaemic limbs after arterial occlusion. We used a transgenic mouse line in which VEGF is inducibly knocked out in skeletal muscle cells (ACTA1‐rtTA, tetO‐Cre, VEGF‐LoxP mice), to test the hypothesis that lack of VEGF‐A hinders the recovery of blood flow after ischaemia. In adult triple transgenic mice, homozygous for VEGF‐LoxP (ACLL mice), skeletal muscle specific VEGF‐A knockout was achieved by dosing with doxycycline (+Dox) for 10 weeks. They then underwent unilateral hindlimb ischaemia surgery under isoflurane anesthesia. Blood flow to the hindpaws was monitored by laser speckle imaging. The ratio of blood flow in the ischaemic to contralateral limb was significantly improved when compared to ACLL mice dosed with vehicle alone (0.81±0.09 +Dox vs 0.47±0.05 ‐Dox at day 21; p<0.001). Although there was no difference in capillary density (mean±SEM, mm −2 ) between these groups of mice (334±24 +Dox vs 261±21 ‐Dox, p>0.05), the arteriole density was significantly higher in ACLL +Dox mice (41±6 +Dox vs 20±2 ‐Dox, p<0.01). Exogenous administration of VEGF by local injection of adenovirus over‐expressing VEGF‐A 165 a to ACLL +Dox mice, inhibited the increase in blood flow recovery (p<0.01). Injection of a control virus (Ad.eGFP) did not affect the rate of recovery after ischaemia in ACLL +Dox mice. These results suggest that VEGF of skeletal muscle origin is detrimental, not beneficial, to arteriolargenesis (the growth of new arterioles). Support or Funding Information Medical Research Council and British Heart Foundation