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Collateral Development in Lower Limb Ischemia Is Impaired by Diabetes

Junhang Zhang, Andreas Bartely, Claes-Göran Östensson, Eric Wahlberg.
Karolinska Institute, Stockholm, Sweden.

OBJECTIVES: Diabetic disease is a strong risk factor for developing Peripheral Arterial Disease (PAD) and patients with leg ischemia and diabetes face a higher risk for deterioration compared with non-diabetic patients. The explanation for this is probably multifactorial but presently unknown. We have previously found that diabetic patients with claudication have fewer collateral vessels than non-diabetic claudicants and therefore hypothesized that a disturbed arteriogenesis process could be one important contributing mechanism to the poor leg prognosis. The purpose of this study was to determine whether diabetes impairs development of collateral vessels in response to tissue ischemia.

METHODS: Goto-Kakisaki (GK) diabetes rats and Wistar rats (Control) were used (6 rats/group). The GK rat is a spontaneous genetic model of non-insulin-dependent (type II) diabetes mellitus. Rats underwent a two-stage surgical procedure in the left leg to produce severe foot ischemia without tissue loss, with the right serving as control. After 28 days rats underwent angiography and LD imaging. The former was used to quantitate the number of new arteries bypassing the occlusion and the latter to provide perfusion data was expressed as percentage of the ischemic relative to the control leg. Tissue biopsies of skeletal muscle were also obtained for immunostaining and measurements of cytokine expression patterns.

RESULTS: Foot perfusion was less in GK compared with control rats (48.5%, versus 72.8%, p<0.05). The number of collaterals on the angiograms was also significantly (p<0.05) decreased in diabetes rats (2.3±0.71 and 5±0.89, respectively). This was supported by the finding of a lower (p<0.05) number of vessels larger than 10 μm (α-actin staining) in adductor muscles of diabetic rats (3.1±0.83 versus 6.7±1.08, per field of view). Furthermore, immunostaining with ki67, a proliferation-associated protein, also indicated a decreased expression in SMCs of the vessel wall in GK rats.

CONCLUSIONS: The collateral development process is impaired in this diabetic rat model and this may be a partial explanation for the poor leg prognosis in patients with diabetes. Ongoing analysis of tissue samples from this study may identify mechanisms responsible for defective arteriogenesis that could be targeted by treatment in the future.