Background
Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex‐specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells.
Methods and Results
Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real‐time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of
BMP7
(bone morphogenetic protein 7) and downstream
IL17Rb (interleukin 17 receptor b)
, with increased transforming growth factor‐β1 (
Tgf‐β1)
and transforming growth factor‐β receptor 1 (
Tgfβ‐r1)
. There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of
Tgf‐β1
,
Tgfβ‐r1
,
and
Col1
with increased migration.
Conclusions
In female AVFs, there is decreased gene expression of
BMP7
and
IL17Rb
with increased
Tgf‐β1
and
Tgfβ‐r1
, and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.
Krüppel-like Factor 4 (KLF4/GKLF) Is a Target of Bone Morphogenetic Proteins and Transforming Growth Factor β1 in the Regulation of Vascular Smooth Muscle Cell Phenotype