Regressed three-dimensional capillary network and inhibited angiogenic factors in the soleus muscle of non-obese rats with type 2 diabetes

Hiroyo Kondo,Fumiko Nagatomo,Akihiko Ishihara,Hidemi Fujino,Roland R Roy,Shinichiro Murakami

doi:10.1186/1743-7075-8-77

Abstract

Based on findings obtained using two-dimensional capillary analyses on tissue cross-sections, diabetes has been shown to be associated with a high risk for microangiopathy and capillary regression in skeletal muscles. We visualized the three-dimensional architecture of the capillary networks in the soleus muscle of non-obese Goto-Kakizaki (GK) rats with type 2 diabetes and compared them with those of control Wistar rats to provide novel information, e.g., capillary volume, on the capillary networks. In addition, we examined pro- and anti-angiogenic gene expression levels in the soleus muscle of GK rats using TaqMan probe-based real-time PCR. As expected, plasma glucose levels were higher and insulin levels lower in GK than control rats. The three-dimensional architecture of the capillary networks was regressed and capillary volume was smaller in the soleus muscle of GK compared to control rats. The mRNA expression levels of the pro-angiogenic factors HIF-1α, KDR, Flt-1, ANG-1, and Tie-2 were lower, whereas the level of the anti-angiogenic factor TSP-1 was higher in GK than control rats. These data suggest that a decrease in pro-angiogenic and increase in anti-angiogenic factors may play an important role in type 2 diabetes-induced muscle circulatory complications.

Highlights

Skeletal muscle homeostasis and function are dependent on adequate blood flow, oxygen delivery, and substrate exchange at the capillary level
Using three-dimensional analyses visualized by confocal laser microscopy, we found a regression of the capillary networks in the soleus muscle of GK compared to control rats
We provide novel information on a decreased capillary volume, lower levels of pro-angiogenic factors, and a higher level of an anti-angiogenic factor in the soleus muscle of GK compared to control rats

Summary

Introduction

Skeletal muscle homeostasis and function are dependent on adequate blood flow, oxygen delivery, and substrate exchange at the capillary level. Microvascular complications are major risk factors associated with diabetes [1]. The degenerative alterations in the capillary networks observed in muscles of diabetic subjects impair blood flow, oxygen delivery, and substrate exchange and can lead to serious conditions, such as diabetic foot ulcers, gangrene, and amputation [2]. It is known that skeletal muscles in animal and human subjects with type 1 or 2 diabetes have impaired angiogenesis and a reduced capillary network [3,4,5]based on two-dimensional analyses on tissue cross sections. No data are available from three-dimensional capillary analyses that would provide novel information, such as changes in capillary volume.

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