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9. Effect of sex differences in treatment response to angioplasty in a murine arteriovenous fistula model.

Author

Chuanqi Cai, Chenglei Zhao, Kilari, Sreenivasulu, Sharma, Amit, Singh, Avishek K., Simeon, Michael L., Misra, Avanish, Yiqing Li, and Misra, Sanjay

Subjects
ARTERIOVENOUS fistula, TRANSLUMINAL angioplasty, ARTERIAL catheterization, JUGULAR vein, CHRONIC kidney failure
Abstract

Failure to mature and venous neointimal hyperplasia formation are the two major causes of hemodialysis arteriovenous fistula (AVF) vascular access failure. Percutaneous transluminal angioplasty (PTA) is the firstline treatment for both of these conditions, but, clinically, women have decreased patency rates compared with men. The hypothesis to be tested in the present study was that female mice after PTA of venous areas of higher intimal thickening have increased gene expression of transforming growth factor-β1 (TGF-β1) and TGF-β receptor 1 (TGFβ- R1) accompanied with histological changes of fibrosis compared with male mice. Seventeen male and eighteen female C57BL/6J mice were used in this study. Chronic kidney disease was induced by partial nephrectomy, and, 28 days later, an AVF was created to connect the left carotid artery to the right jugular vein. Two weeks later, the higher intimal thickening area was treated with PTA, and mice were euthanized 3 days later for gene expression analysis or 14 days later for histopathological analysis. Doppler ultrasound was performed weekly after AVF creation. At day 3, female AVF had significantly higher average gene expression of TGF-β1 and TGFβ-R1 compared with male AVF. At day 14, female outflow veins had a smaller venous diameter, lumen vessel area, decreased wall shear stress, lower average peak systolic velocity, and an increased neointima area-to-media area ratio. Moreover, female outflow veins showed a significant increase in α-smooth muscle actin and fibroblast-specific protein-1. There was a decrease in M1/M2 with an increase in CD68. [ABSTRACT FROM AUTHOR]

Published
2020
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10. Abstract 16142: Increased TGF?1 Signaling, Fibrosis and Circulating Cell Infiltration of Female Graft Veins Contribute to Sex Differences in Murine Arteriovenous Fistulas

Author

Cai, Chuanqi, Zhao, Chenglei, Kilari, Sreenivasulu, Sharma, Amit, Yang, Binxia, Avishek, Singh, Michael, Simeon, Misra, Avanish, Yiqing, Li, Kumar, Rajiv, and Misra, Sanjay

Abstract

Introduction:Arteriovenous fistula (AVF) maturation and patency rates are decreased in women as a result of poorly defined processes. To illustrate the sexual diversities among female and male fistulas and to unveil potential mechanism we created a clinically relevant murine AVF model.Hypothesis:Sexual disparity between female and male murine AVFs is not due to inherent vascular morphometric differences but linked to distinct vascular remodeling patterns after AVF creation.Methods:Four weeks after partial nephrectomy surgery 18 female and 19 male C57BL/6J wild type (WT) mice underwent native AVF (n-AVF) surgeries by anastomosis end-jugular vein to side-contralateral-carotid artery. Another 26 transplanted AVF (t-AVF) surgeries were established by embedding donor inferior vena cava (IVC) from WT or global GFP mice into gender matched recipient GFP or WT n-AVF. Native graft vein (NGV) and transplanted graft vein (TGV) were collected for gene expression and histopathological assay. AVF patency and hemodynamic parameters were monitored by noninvasive Doppler detection weekly.Results:Female NGVs had significantly decreased peak velocity (PV), lumen vessel area, neointimal area and neointimal cell density than males. There were significant increases in TGF?1 (p<0.0001) and TGF? receptor1 (p<0.0001) gene expression as well as significant increasing in ?-SMA (p<0.05), FSP-1 (p<0.05), Collagen I (p<0.05) and pSMAD3 (p<0.05) protein expression in female NGVs. In female t-AVFs at day 14, reduced PV was due to remodeling of the vessel wall from circulating cells (from inside to outside). In contrast, in t-AVFs of male mice 14 days after t-AVF creation, neointimal lesions showed cellular accumulation originating from resident tissue cells (remodeling from outside to inside).Conclusions:Decreased AVF performance in female mice compared to male mice was not due to inherent diameter and hemodynamic parameters but rather an increase in TGF?1 signaling, fibrosis and infiltration of the fistula wall by circulating cells. These results provide valuable insights into the mechanisms of female detrimental outcomes which are linked to distinct vascular remodeling patterns occurring as early as 2 weeks after AVF creation.

Published
2019
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