Regulation of the ALK1 ligands, BMP9 and BMP10

Li, Wei; Salmon, Richard M.; Jiang, He; Morrell, Nicholas W.

doi:10.1042/bst20160083

Cited by 40 publications

(27 citation statements)

References 54 publications

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“…TGF-b signaling at the BBB is facilitated by transmembrane serine-threonine kinase receptors [i.e., activin receptor-like kinase (ALK)-1 and ALK5]. ALK1 and ALK5 constitute the primary TGF-b receptors that mediate vascular remodeling and angiogenesis (Oh et al, 2000) and have been shown to induce opposite effects at the BBB (Lebrin et al, 2005;Ronaldson et al, 2009;Curado et al, 2014;Wei et al, 2014;Li et al, 2016). Effects of TGF-b/ALK1 signaling at the BBB can be studied using the well-characterized ALK1 receptor agonist bone morphogenetic protein 9 (BMP-9) (Brown et al, 2005;Herrera et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

et al. 2018

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Central nervous system (CNS) drug delivery can be achieved by targeting drug uptake transporters such as Oatp1a4. In fact, many drugs that can improve neurologic outcomes in CNS diseases [3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (i.e., statins)] are organic anion transporting polypeptide (OATP) transport substrates. To date, transport properties and regulatory mechanisms of Oatp1a4 at the blood-brain barrier (BBB) have not been rigorously studied. Such knowledge is critical to develop Oatp1a4 for optimization of CNS drug delivery and for improved treatment of neurological diseases. Our laboratory has demonstrated that the transforming growth factor-b (TGF-b)/activin receptor-like kinase 1 (ALK1) signaling agonist bone morphogenetic protein 9 (BMP-9) increases functional expression of Oatp1a4 in rat brain microvessels. Here, we expand on this work and show that BMP-9 treatment increases blood-to-brain transport and brain exposure of established OATP transport substrates (i.e., taurocholate, atorvastatin, and pravastatin). We also demonstrate that BMP-9 activates the TGF-b/ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Overall, this study provides evidence that Oatp1a4 transport activity at the BBB is directly regulated by TGF-b/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of OATP substrate drugs.

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Section: Introductionmentioning

confidence: 99%

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

et al. 2018

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“…The proangiogenic effects of several members of this family are mediated via activin receptor-like kinase 1 (ALK1), a type I receptor [2], which has been shown to be essential for vascular development, remodeling and pathological angiogenesis. Although multiple BMPs can activate ALK1, BMP9 and BMP10 are specific activators in endothelial cells [3]. …”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

et al. 2017

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Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.

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“…BMPs are involved in many different biological activities, during both embryonic development and adult life, and control, in particular, the vascular system homeostasis . BMPs are dimeric polypeptides that are generally secreted in association with their processed precursor part, producing either active or latent complexes . BMPs transduce their biological signal from the cell surface through binding to two different types of serine/threonine kinase receptors (RI, also named activin receptor‐like kinase [ALK], and RII), subsequent phosphorylation of the intracellular transcription factor Smad1, Smad5, or Smad9, and translocation of these phospho‐Smads in complex with Smad4 to the nucleus, where they regulate the transcription of target genes.…”

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confidence: 99%

Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis

et al. 2019

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Bone morphogenetic protein 9 (BMP9) is a circulating factor produced by hepatic stellate cells that plays a critical role in vascular quiescence through its endothelial receptor activin receptor-like kinase 1 (ALK1). Mutations in the gene encoding ALK1 cause hereditary hemorrhagic telangiectasia type 2, a rare genetic disease presenting hepatic vessel malformations. Variations of both the circulating levels and the hepatic mRNA levels of BMP9 have been recently associated with various forms of hepatic fibrosis. However, the molecular mechanism that links BMP9 with liver diseases is still unknown. Here, we report that Bmp9 gene deletion in 129/Ola mice triggers hepatic perisinusoidal fibrosis that was detectable from 15 weeks of age. An inflammatory response appeared within the same time frame as fibrosis, whereas sinusoidal vessel dilation developed later on. Proteomic and mRNA analyses of primary liver sinusoidal endothelial cells (LSECs) both revealed that the expression of the LSEC-specifying transcription factor GATA-binding protein 4 was strongly reduced in Bmp9 gene knockout (Bmp9-KO) mice as compared with wild-type mice. LSECs from Bmp9-KO mice also lost the expression of several terminal differentiation markers (Lyve1, Stab1, Stab2, Ehd3, Cd209b, eNos, Maf, Plvap). They gained CD34 expression and deposited a basal lamina, indicating that they were capillarized. Another main characteristic of differentiated LSECs is the presence of permeable fenestrae. LSECs from Bmp9-KO mice had a significantly reduced number of fenestrae. This was already observable in 2-week-old pups. Moreover, we could show that addition of BMP9 to primary cultures of LSECs prevented the loss of their fenestrae and maintained the expression levels of Gata4 and Plvap. Conclusion: Taken together, our observations show that BMP9 is a key paracrine regulator of liver homeostasis, controlling LSEC fenestration and protecting against perivascular hepatic fibrosis.

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Regulation of the ALK1 ligands, BMP9 and BMP10

Cited by 40 publications

References 54 publications

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis

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