The role of BMPs in endothelial cell function and dysfunction

Abstract

The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. In embryonic development, BMPs promote endothelial specification and subsequent venous differentiation. The BMP pathway also plays important roles in the adult vascular endothelium, promoting angiogenesis and mediating shear and oxidative stress. The canonical BMP pathway functions through the Smad transcription factors; however, other intracellular signaling cascades can be activated, and receptor complexes beyond the traditional type I and type II receptors add additional layers of regulation. Dysregulated BMP signaling has been linked to vascular diseases including pulmonary hypertension and atherosclerosis. This review addresses recent advances in the roles of BMP signaling in the endothelium and how BMPs affect endothelial dysfunction and human disease.

Figure 1. An overview of the canonical BMP pathway

(A) In the absence of BMP binding (top panel), BMP receptors type I and II do not associate, and the Smad transcription factors remain in the cytoplasm. (B) BMP typically binds to the type II receptor (bottom panel), which allows type I and II receptors dimerize and the type II receptor to phosphorylate the type I receptor. However, in some cases, the BMP ligand has a higher affinity for the type I receptor, and this binding will then induce dimerization and subsequent phosphorylation. This phosphorylation of the type I receptor leads to the phosphorylation of downstream Smads, canonically Smads 1/5/8, which then associate with the co-Smad, Smad4, and translocate into the nucleus. The Smad complex will bind to BMP response elements and induce the transcription of downstream targets. (C) The recently discovered type III receptors can compete with the type II receptors and form a complex with the type I receptors. This association leads to endocytosis-mediated recycling of the ligand-receptor complex to the membrane, which amplifies the BMP signaling pathway. (D–F) Although the canonical pathway is seemingly straightforward, a single ligand can have numerous effects and outcomes in endothelial cells. Depicted here are the effects of BMP2 (D), BMP4 (E), and BMP9 (F) specifically via BMPRII. Each ligand can signal through the canonical Smad1 or through a different intracellular cascade. Further, even a single ligand can have opposing effects on a single behavior (e.g., BMP9 and proliferation) via the intracellular signaling cascade that is activated. For simplicity, type I and type III receptors, if identified, as well as downstream targets have been omitted.