Role of ADTRP (Androgen‐Dependent Tissue Factor Pathway Inhibitor Regulating Protein) in Vascular Development and Function

Abstract

Background The physiological function of ADTRP (androgen‐dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function. Methods and Results Genetic inhibition of Adtrp produced vascular malformations in the low‐pressure vasculature of zebrafish embryos and newborn mice: dilation/tortuosity, perivascular inflammation, extravascular proteolysis, increased permeability, and microhemorrhages, which produced partially penetrant lethality. Vascular leakiness correlated with decreased endothelial cell junction components VE ‐cadherin and claudin‐5. Changes in hemostasis in young adults comprised modest decrease of tissue factor pathway inhibitor antigen and activity and increased tail bleeding time and volume. Cell‐based reporter assays revealed that ADTRP negatively regulates canonical Wnt signaling, affecting membrane events downstream of low‐density lipoprotein receptor‐related protein 6 ( LRP 6) and upstream of glycogen synthase kinase 3 beta. ADTRP deficiency increased aberrant/ectopic Wnt/β‐catenin signaling in vivo in newborn mice and zebrafish embryos, and upregulated matrix metallopeptidase ( MMP )‐9 in endothelial cells and mast cells ( MCs ). Vascular lesions in newborn Adtrp −/− pups displayed accumulation of MCs , decreased extracellular matrix content, and deficient perivascular cell coverage. Wnt‐pathway inhibition reversed the increased mmp9 in zebrafish embryos, demonstrating that mmp9 expression induced by Adtrp deficiency was downstream of canonical Wnt signaling. Conclusions Our studies demonstrate that ADTRP plays a major role in vascular development and function, most likely through expression in endothelial cells and/or perivascular cells of Wnt‐regulated genes that control vascular stability and integrity.

AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice

“…S2F). This finding contrasts with a recent report that described an independently-generated ADTRP-deficient mouse strain that exhibited moderately decreased viability and non-Mendelian offspring ratios (21). We suspect that differences between our knockout strategy, which removed 13-bases from the locus, and that of the reported approach, which deleted approximately 38 kb of the genomic region between exons 3 and 5, might underlie the variance.…”

“…Depletion of ADTRP in endothelial cells reduced TFPI levels, an observation that was attributed to the ability of these two proteins to interact in the plasma membrane (19). More recently, deletion of ADTRP in mice was reported to cause vascular dysfunction, though the mechanism by which this occurs is unclear (21). AIG1 is homologous to ADTRP and was discovered in human dermal papilla cells as an androgen-regulated gene (22).…”

Insights into the Functional Role of ADTRP (Androgen-Dependent TFPI-Regulating Protein) in Health and Disease

“…Figure 3 illustrates examples of ADTRP localization in mouse tissues. The mRNA expression of Adtrp increased significantly (3–4 times) during embryogenesis [ 39 ]. Another group also reported localization of mouse ADTRP in the liver, adipose tissue, kidney, and duodenum [ 40 ].…”

“…In zebrafish, we showed by in-situ hybridization that adtrp is expressed in the lateral plate mesoderm, most likely in angioblasts, and in both the dorsal aorta and cardinal vein [ 39 ]. qPCR revealed that the mRNA expression of adtrp increased up to 50 times during zebrafish embryonic development and into adulthood [ 39 ].…”

“…Wang and colleagues [ 46 ] demonstrated that adtrp1 , one of the two paralogues of zebrafish adtrp , could regulate the specification of hemangioblasts, primitive myelopoiesis, and definitive hematopoiesis. According to the NCBI-2013 database, adtrp1 ( zgc112175 ) is the only gene homologous to human ADTRP [ 39 ]. Using morpholino-mediated knockdown as well as overexpression of adtrp1 , Wang et al [ 46 ] showed that adtrp1 regulates the expression of tfpi and consequently the specification of hemangioblasts and hematopoiesis.…”