gms | German Medical Science

Accelerated cardiovascular end organ damage causes substantial mortality and morbidity in patients with chronic renal failure. Angiogenesis is an important mechanism to maintain tissue perfusion in the face of vascular disease. We tested the hypothesis that chronic renal failure impairs ischemia-induced angiogenesis in the skeletal muscle circulation of rats.

Twenty male Sprague-Dawley rats underwent subtotal nephrectomy (5/6NX) by surgical ablation, or sham surgery (n=10 each). Ten weeks thereafter, unilateral hindlimb ischemia was induced in all animals by ligation and excision of the left common femoral artery. Animals were sacrificed two weeks later. Capillary density was assessed by immunostaining for CD31. Limb perfusion was measured by a Laser Doppler Perfusion Imager, and by the fluorescent microsphere technique. The expression of vascular endothelial growth factor-1 (VEGF) and its receptors was evaluated by real-time RT-PCR.

Rats with 5/6NX exhibited renal failure but remained normotensive (mean arterial pressure 110±5 mmHg versus 106±5 in controls, p>0.1). Ischemia-induced neovascularization was significantly impaired in 5/6NX compared to sham operated rats (average increase in capillary density versus non-ischemic hindlimb: 29.±67% in 5/6NX versus 69±8% in controls, p<0.05). Hindpaw perfusion measured by the Laser Doppler technique 14 days after ligation was lower in 5/6NX than in control rats (59±6% versus 79±4% of flow in non-ischemic limbs, respectively, p<0.05). Furthermore, hindlimb muscle perfusion as assessed by fluorescent microspheres was impaired in renal failure (relative perfusion of ischemic muscle compared to non-ischemic muscle: 69±6% in 5/6NX versus 92±4% in control rats, p<0.01). VEGF as well as VEGF receptor 1 (Flt1) and 2 (Flk1) mRNA increased in ischemic hindlimbs of control rats whereas it remained unaltered or decreased in 5/6NX animals (change of VEGF expression in ischemic muscle, compared with non-ischemic muscle: -2±9% in 5/6NX versus +37±12% in control animals).

We conclude that chronic renal failure impairs angiogenesis and perfusion in the skeletal muscle circulation of rats. Impaired angiogenesis may contribute to the burden of peripheral arterial disease in patients with renal failure.