BMPER Promotes Epithelial-Mesenchymal Transition in the Developing Cardiac Cushions

Abstract

Formation of the cardiac valves is an essential component of cardiovascular development. Consistent with the role of the bone morphogenetic protein (BMP) signaling pathway in cardiac valve formation, embryos that are deficient for the BMP regulator BMPER (BMP-binding endothelial regulator) display the cardiac valve anomaly mitral valve prolapse. However, how BMPER deficiency leads to this defect is unknown. Based on its expression pattern in the developing cardiac cushions, we hypothesized that BMPER regulates BMP2-mediated signaling, leading to fine-tuned epithelial-mesenchymal transition (EMT) and extracellular matrix deposition. In the BMPER-/- embryo, EMT is dysregulated in the atrioventricular and outflow tract cushions compared with their wild-type counterparts, as indicated by a significant increase of Sox9-positive cells during cushion formation. However, proliferation is not impaired in the developing BMPER-/- valves. In vitro data show that BMPER directly binds BMP2. In cultured endothelial cells, BMPER blocks BMP2-induced Smad activation in a dose-dependent manner. In addition, BMP2 increases the Sox9 protein level, and this increase is inhibited by co-treatment with BMPER. Consistently, in the BMPER-/- embryos, semi-quantitative analysis of Smad activation shows that the canonical BMP pathway is significantly more active in the atrioventricular cushions during EMT. These results indicate that BMPER negatively regulates BMP-induced Smad and Sox9 activity during valve development. Together, these results identify BMPER as a regulator of BMP2-induced cardiac valve development and will contribute to our understanding of valvular defects.

Loss of Bone Morphogenetic Protein-binding Endothelial Regulator Causes Insulin Resistance

“…Our previous studies [10][11][12][13][14][15] suggest that BMPER is highly expressed in vascular endothelial cells (ECs). To determine whether EC is an important source for BMPER production, we generated endothelium-specific BMPER inducible knockout (eKO) mice by breeding BMPER flox/flox and Cdh5-CreER +/mice.…”

“…BMPER (also called CV-2) binds BMPs and is an extracellular modulator of BMP signaling pathway 9 . We have discovered BMPER plays a pivotal role in BMP-mediated endothelial events and chronic inflammation in the vasculature [10][11][12][13][14][15] . However, the role of BMPER in obesity and insulin resistance has not been studied before.…”

Increased Expression of Gremlin1 Promotes Proliferation and Epithelial Mesenchymal Transition in Gastric Cancer Cells and Correlates With Poor Prognosis of Patients With Gastric Cancer

“…Regulation of EMT by BMPs has been implicated in many studies regarding organ development (30,31) and cancer (32)(33)(34)(35). BMPs can induce EMT by both Smad-dependent (36)(37)(38) and Smad-independent pathways (39,40). For instance, BMP signalling could directly activate the expression of the EMT transcription factors, Snail, TWIST1 and MSX1/2 (36)(37)(38).…”

“…BMPs can induce EMT by both Smad-dependent (36)(37)(38) and Smad-independent pathways (39,40). For instance, BMP signalling could directly activate the expression of the EMT transcription factors, Snail, TWIST1 and MSX1/2 (36)(37)(38). Regarding the Smad-independent pathway, BMP2 could induce EMT and invasion through regulation of the PI3K/Akt pathway (39,40).…”

Overexpression of BMPER in Ovarian Cancer and the Mechanism by which It Promotes Malignant Biological Behavior in Tumor Cells

“…The human BMPER gene is located on chromosome 7p14.3. BMPER can affect biological behaviors such as differentiation, proliferation and migration of vascular endothelial cells, regulate angiogenesis, and participate in the development of various organs such as bone, lung, kidney, and some associated diseases[6,[14][15][16]. Our team used…”