Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins

Abstract

Arteries and veins have very different susceptibility to certain vascular diseases such as atherosclerosis and vascular calcification. The molecular mechanisms of these differences are not fully understood. In this study, we discovered that COUP-TFII, a transcription factor critical for establishing the venous identity during embryonic vascular development, also regulates the pathophysiological functions of adult blood vessels, especially those directly related to vascular diseases. Specifically, we found that suppression of COUP-TFII in venous ECs switched its phenotype toward pro-atherogenic by up-regulating the expression of inflammatory genes and down-regulating anti-thrombotic genes. ECs with COUP-TFII knockdown also readily undergo endothelial-to-mesenchymal transition (EndoMT) and subsequent osteogenic differentiation with dramatically increased osteogenic transcriptional program and calcium deposition. Consistently, over-expression of COUP-TFII led to the completely opposite effects. In vivo validation of these pro-atherogenic and osteogenic genes also demonstrates a broad consistent differential expression pattern in mouse aorta vs. vena cava ECs, which cannot be explained by the difference in hemodynamic flow. These data reveal phenotypic modulation by different levels of COUP-TFII in arterial and venous ECs, and suggest COUP-TFII may play an important role in the different susceptibilities of arteries and veins to vascular diseases such as atherosclerosis and vascular calcification.

Evaluation of late outgrowth endothelial progenitor cell and umbilical vein endothelial cell responses to thromboresistant collagen‐mimetic hydrogels

“…These EphrinB2:EphB4 ratio results may suggest increased EOC progression toward an arterial (versus venous) EC phenotype on PEG‐Scl2‐2 hydrogels, although further phenotypic and functional assessments would be required for definitive statements to be made. However, an increased arterial phenotype would be desirable for EOC use in coronary artery applications, as important functional differences are known to exist between arterial and venous ECs . Finally, although Col IV is a natural component of the arterial basement membrane, it is possible—if confluence of the endothelial layer is disrupted—that the Col IV deposited by the EOCs and HUVECs could be exposed to blood and induce thrombus formation.…”

Atherosclerosis-associated differentially methylated regions can reflect the disease phenotype and are often at enhancers

“…TBX18 is implicated in the generation of SMCs during development [40] and was reported to be induced in the endothelial layer of atherosclerotic arteries [44]. NR2F2 is associated with phenotypic switching in vein endothelial cells [45]. These two genes displayed athero hypometh DMRs which suggests disease-linked upregulation of expression because they overlap a promoter or enhancer-type region in aorta.…”

NR2F2 regulates chondrogenesis of human mesenchymal stem cells in bioprinted cartilage

“…Although, our previous work showed a synergistic growth factor treatment of the bioprinted constructs at initial chondrocyte seeding density at 8 million cells/mL with better cartilage formation even comparing to the higher cell seeding density at 20 million cells/mL (Cui et al, ), a similar approach to stimulate MSCs proliferation and differentiation in bioprinted tissues still remains unsatisfactory due to the lack of ECM production and hypertrophy of differentiated cells. We previously observed endothelial cells with NR2F2 knockdown readily underwent endothelial‐to‐mesenchymal transition (EndoMT) and subsequent osteogenic differentiation (Cui et al, ). Consistently, over‐expression of NR2F2 led to the completely opposite effects.…”