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Angiogenesis in human parathyroid disease and chronic allograft nephropathy

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MitchellDRI_2007redux.pdf (27.06Mb)
Date
2007
Author
Mitchell, David R. I.
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Abstract
 
 
Angiogenesis in parathyroid disease and association with VEGF
 
Angiogenesis has been demonstrated in normal parathyroid tissue in vitro and must occur in vivo to allow for successful transplantation. Here we present data that angiogenesis also occurs in parathyroid disease states and that VEGF (a known endothelial cell mitogen) expression is not evident in these tissues.
 
Formalin fixed, paraffin embedded sections of human parathyroid tissue were stained with an antibody to CD31 to visualise endothelial cells and separate sections stained with antibody to VEGF using standard immunohistochemistry techniques. Microvessel counts were performed by two (blinded) investigators. Western blot analysis of protein lysate of parathyroid tissue was also performed using antibody to VEGF.
 
123 patients were studied (44 normal, 27 hyperplasia and 52 adenoma). Microvessel counts showed a statistically significant (p < 0.05 compared with normal) and step-wise increase in microvessel count between the different types of tissue. 120 parathyroid sections stained with antibody to VEGF with positive control of normal kidney showed non-specific staining in all tissue types, a finding which was repeated with Western blot analysis of protein derived from 1 normal, 2 adenomas and 2 hyperplasia samples.
 
Here we have demonstrated evidence of angiogenesis that occurs in human parathyroid tissue when diseased. Our data have not shown a significant expression ofVEGF in these samples. This finding implies that either VEGF does not mediate angiogenesis in these tissues or that it does so transiently. Alternatively VEGF may act in concentrations too small to be detected with these techniques. Gaining a better understanding ofthe progression of angiogenesis in parathyroid disease may lead to the development of novel therapeutic strategies.
 
Changes in Vascularity Associated with Chronic Allograft Nephropathy
 
This study aims to compare vascularity of kidneys with CAN versus normal. In addition, validation of renal biopsy samples in the assessment of angiogenesis has been performed.
 
Tissue from transplant nephrectomies performed because of CAN (n=29), antecedent biopsies from these grafts (n=18) and normal kidneys (n=61) were studied. Protocol renal transplant biopsies were also studied. Tissue sections were immunostained with the endothelial cell antibody to CD31. Changes in overall vascular patterns were noted and microvessel counts performed. Sections were dual-stained with antibody to CD31 and the proliferation marker, MIB-1, to determine the presence of proliferating endothelial cells. Microvessel counts were performed on paired samples of core biopsies and cross-section of normal kidney and were compared in early protocol biopsy specimens from grafts which develop CAN (n=10) with those where stable graft function continued (n=20). Macrophage infiltration was studied using immunostaining to CD68.
 
CD31 staining from CAN nephrectomies exhibited diminished cortical and medullary staining and was accompanied by a significant increase in proliferation index when compared with normal. There was significant correlation in microvessel counts in core biopsies and the corresponding kidney crosssection. Early biopsies from grafts which developed CAN show significantly higher microvessel counts compared with the corresponding nephrectomy. The number ofproliferating ECs was significantly increased in this biopsy group compared with normal kidney but was not significantly different compared with the CAN nephrectomy group. Early protocol biopsies from grafts which developed CAN showed significantly higher microvessel counts compared with those with stable graft function. A significant increase in macrophage infiltration was seen in CAN nephrectomies compared with normal kidney.
 
This study demonstrates reduced density of CD31-positive microvessels in CAN compared with normal. In addition, the investigation of changes in the microvasculature in CAN by study of core biopsies has been validated and confirms preservation of normal vasculature in early CAN. Together with evidence ofproliferating endothelial cells these findings support a hypothesis that, early in the development ofCAN, angiogenesis is stimulated, but despite this attempt at tissue repair, progressive microvascular loss occurs. The presence of significant numbers of macrophages may be of aetiological importance or reflect changes relating to cessation of immunosuppression.
 
URI
http://hdl.handle.net/1842/29280
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