BMPs go for apelin to regulate angiogenesis. Focus on "inhibition of apelin expression by BMP signaling in endothelial cells".

OVER THE PAST 30 YEARS, THERE has been considerable interest in the elucidation of factors that mediate angiogenesis. These efforts led to the identification of factors such as vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factor (FGF-1 and -2), and angiopoietins, to name a few. Subsequent detailed investigations have revealed that finely tuned and precisely coordinated expression of these factors is critical for angiogenesis during both development and adult life. Failure to coordinate expression has significant implications, as excess angiogenesis can contribute to tumor growth and inflammatory disorders, whereas insufficient angiogenesis can contribute to ischemic heart disease or preeclampsia. More recently, additional factors, including Notch, Wnt, and morphogens such as bone morphogenetic proteins (BMPs), have emerged as critical regulators for proper blood vessel formation. BMPs, members of the transforming growth factor(TGF) superfamily, were originally identified as factors that induce the formation of bone and cartilage when implanted at ectopic sites (8). BMPs bind to type I and type II serine-threonine kinase membrane receptors, and transduce signals through Smad (Smad1/5/8 and Smad4) and non-Smadsignaling pathways. The role of BMPs in vascular development has been illustrated by studies in knockout animals (Bmp2, Bmp4, Bmp9, Bmpr2, Alk1, Alk3, endoglin). Recently, the identification of BMP9 and BMP10, as physiological ligands of high affinity for the type I receptor ALK1, which is specifically expressed on endothelial cells, reinforced evidence for BMPs in angiogenesis (3). In this issue of the American Journal of Physiology-Cell Physiology, Poirier et al. (10) used a genomic approach for identifying BMP target genes in endothelial cells and identified the adipokine apelin. They found that BMP4, BMP7, and BMP9 inhibit apelin expression in human microvascular endothelial cells from the dermis, BMP9 having the strongest inhibitory activity. Two other very recent studies also reported an inhibitory effect of BMP9 on apelin expression, i.e., in human pulmonary artery endothelial cells (HPAEc; 11) and human umbilical vein endothelial cells (HUVEC; 7). In contrast, another study recently showed that BMP2 slightly increases apelin expression in HPAEc and that a siRNA directed against BMP type 2 receptor (BMPR2) decreases basal apelin expression (1). Further work will be necessary to reconcile these apparently contradictory data. Many transcription factors that may regulate apelin gene expression have been reported. The data of Poirier et al. demonstrate that Smads, which are transcription factors of the TGFfamily, are involved in BMP-mediated inhibition of apelin expression. They further showed that this inhibition does not require protein synthesis and that it is transcriptional although no promoter element could be identified. Apelin was originally identified as the ligand for APJ (angiotensin II receptor-like 1, Agtrl1, Xmsr), a 7-transmembrane G protein-coupled orphan receptor (5). Apelin is synthesized as a 77-amino acid preproprotein expressed primarily in endothelial cells that is cleaved to a number of active peptides by proteases. APJ is expressed in endothelial cells, vascular smooth muscle cells, and cardiomyocytes. Recent evidence suggests that APJ may function, in some contexts, independently of its ligand. Indeed, Scimia et al. (12) reported that APJ can be activated by stretch, which increases cardiac hypertrophy in a G protein-independent manner. Apelin has pleiotropic functions and has been shown to regulate vascular tone, blood pressure, angiogenesis, and cardiac remodeling. In vitro analysis revealed that the apelin-APJ system regulates angiogenesis by the induction of proliferation, migration, inhibition of apoptosis of cultured endothelial cells, and increased vessel caliber (6). Interestingly, expression of apelin and APJ genes is upregulated during blood vessel development and downregulated in stabilized vasculature. Poirier et al. (10) showed that apelin expression blocked the inhibitory effects of BMPs on endothelial cell proliferation, suggesting that apelin could be an important mediator of BMP in angiogenesis. The working model would be that BMPs repress apelin expression and thus apelin would not be able to increase endothelial cell functions, such as proliferation and migration, and would allow the maturation phase of angiogenesis to take place (Fig. 1). In accordance with this model, one