Early onset of fibrosis within the arterial media in a rat model of type 2 diabetes mellitus with erectile dysfunction.
OBJECTIVE
To determine, in the obese Zucker fa/fa rat (OZR), whether the loss in smooth muscle cells (SMCs) as well as the increase in fibrosis that occurs within the corpora cavernosa accompanying corporal veno-occlusive dysfunction (CVOD), also occurs within the media of the arterial tree.


METHODS
The penis and aorta from both 7-month-old male diabetic OZR (5 months of diabetes) and aged-matched nondiabetic lean Zucker rats (LZR) rats were harvested (eight per group). The penis and aorta were subjected to histo- or immnohistochemistry, followed by quantitative image analysis (QIA) to determine the contents of SMC, collagen and the pro-fibrotic transforming growth factor (TGF)beta1. The turnover of SMCs was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) assays. Quantitative Western blots determined calponin (SMC marker) and PCNA, and hydroxyproline was used for collagen. In vitro relaxation of corporal strips was measured.


RESULTS
In vitro relaxation of corporal tissue from OZR was considerably less than in the LZR. In the media of the penile dorsal artery (PDA) of OZR, there was a considerable reduction in the SMC content and the SMC/collagen ratio, as well as an increase in apoptosis, but there were no changes in PCNA or TGFbeta1 expression, or in the intima-media/lumen ratio. In the aorta of the OZR, in contrast to the PDA, there was a reduction in PCNA as well as a more pronounced decrease in the SMC/collagen ratio, mainly from an increase in collagen, but there were no changes in TGFbeta1 or the wall/lumen morphometry. In the OZR, Western blots of aortic tissue confirmed the decrease in PCNA and a reduction in the SMC marker calponin.


CONCLUSIONS
These data show that 5 months after the onset of hyperglycaemia in the OZR, the rats develop both abnormal corporal SMC relaxation and a generalized fibrosis of the arterial media of both the large and small diameter vessels. It is possible that this pan-fibrosis of the media of the arterial system might contribute to the diabetes-related ED that occurs during this period in this rat model.
Kovanecz
Istvan
I
Division of Urology at Harbor-UCLA Medical Center, Urology Research Laboratory, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA.
Nolazco
Gaby
G
Ferrini
Monica G
MG
Toblli
Jorge E
JE
Heydarkhan
Sanaz
S
Vernet
Dolores
D
Rajfer
Jacob
J
Gonzalez-Cadavid
Nestor F
NF
D000818:Animals; D001011:Aorta / Q000473:pathology*; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D007150:Immunohistochemistry; D018783:Impotence, Vasculogenic / Q000209:etiology / Q000473:pathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010413:Penis / Q000098:blood supply* / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D017540:Tunica Media / Q000473:pathology*