Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling

Nature Cardiovascular Research volume 3, pages 785–798 (2024)Cite this article

Subjects

Abstract

Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: KLF2 mediates high FSS-induced Smad1/5 suppression.
Fig. 2: BMPER suppresses Smad1/5 activation under high FSS.
Fig. 3: AVF model of high FSS-mediated outward remodeling.
Fig. 4: BMPER regulates Akt activation under high FSS.
Fig. 5: BMPER iECKO impairs blood flow recovery in the HLI model.
Fig. 6: BMPER iECKO blocks outward remodeling in the AVF model.
Fig. 7: BMP9/10 blocking Abs restore blood flow recovery in the BMPER iECKO HLI model.
Fig. 8: BMP9/10 blocking Abs improve blood flow recovery and vascular remodeling in diabetic mice.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary Information files. RNAseq data are available from the NCBI Gene Expression Omnibus under accession number GSE267813. ChIP–seq data were deposited in the Gene Expression Omnibus under accession numbers GSE152900 ref. 32 and GSE128382 ref. 33. Source data are provided with this paper.

References

  1. Heusch, G. et al. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 383, 1933–1943 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gibbons, G. H. & Dzau, V. J. The emerging concept of vascular remodeling. N. Engl. J. Med. 330, 1431–1438 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Lucitti, J. L. et al. Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development 134, 3317–3326 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Howangyin, K. Y. & Silvestre, J. S. Diabetes mellitus and ischemic diseases: molecular mechanisms of vascular repair dysfunction. Arter. Thromb. Vasc. Biol. 34, 1126–1135 (2014).

    Article  CAS  Google Scholar 

  5. Spinetti, G., Kraenkel, N., Emanueli, C. & Madeddu, P. Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies. Cardiovasc. Res. 78, 265–273 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Hahn, C. & Schwartz, M. A. Mechanotransduction in vascular physiology and atherogenesis. Nat. Rev. Mol. Cell Biol. 10, 53–62 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baeyens, N. et al. Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. eLife https://doi.org/10.7554/eLife.04645 (2015).

  8. Langille, B. L. & O’Donnell, F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 231, 405–407 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Wong, C. Y. et al. Vascular remodeling and intimal hyperplasia in a novel murine model of arteriovenous fistula failure. J. Vasc. Surg. 59, 192–201 e191 (2014).

    Article  PubMed  Google Scholar 

  10. Tiezzi, M., Deng, H. & Baeyens, N. Endothelial mechanosensing: a forgotten target to treat vascular remodeling in hypertension? Biochem. Pharmacol. https://doi.org/10.1016/j.bcp.2022.115290 (2022).

  11. Deng, H. et al. cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling. Preprint at bioRxiv. https://doi.org/10.1101/2023.10.24.563764 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yang, B., Shergill, U., Fu, A. A., Knudsen, B. & Misra, S. The mouse arteriovenous fistula model. J. Vasc. Interv. Radiol. 20, 946–950 (2009).

    Article  PubMed  Google Scholar 

  13. Browne, L. D. et al. The role of shear stress in arteriovenous fistula maturation and failure: a systematic review. PLoS ONE 10, e0145795 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Manov, J. J., Mohan, P. P. & Vazquez-Padron, R. Arteriovenous fistulas for hemodialysis: brief review and current problems. J. Vasc. Access 23, 839–846 (2022).

    Article  PubMed  Google Scholar 

  15. Lowery, J. W. & de Caestecker, M. P. BMP signaling in vascular development and disease. Cytokine Growth Factor Rev. 21, 287–298 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morrell, N. W. et al. Targeting BMP signalling in cardiovascular disease and anaemia. Nat. Rev. Cardiol. 13, 106–120 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Perera, N., Ritchie, R. H. & Tate, M. The role of bone morphogenetic proteins in diabetic complications. ACS Pharmacol. Transl. Sci. 3, 11–20 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Baeyens, N. et al. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J. Cell Biol. 214, 807–816 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Moser, M. et al. BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation. Mol. Cell. Biol. 23, 5664–5679 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Satomi-Kobayashi, S. et al. Osteoblast-like differentiation of cultured human coronary artery smooth muscle cells by bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER). J. Biol. Chem. 287, 30336–30345 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Moreno-Miralles, I., Ren, R., Moser, M., Hartnett, M. E. & Patterson, C. Bone morphogenetic protein endothelial cell precursor-derived regulator regulates retinal angiogenesis in vivo in a mouse model of oxygen-induced retinopathy. Arter. Thromb. Vasc. Biol. 31, 2216–2222 (2011).

    Article  CAS  Google Scholar 

  22. Pi, X. et al. Bmper inhibits endothelial expression of inflammatory adhesion molecules and protects against atherosclerosis. Arter. Thromb. Vasc. Biol. 32, 2214–2222 (2012).

    Article  CAS  Google Scholar 

  23. Helbing, T. et al. BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium. Blood 118, 5040–5049 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Mao, H. et al. Loss of bone morphogenetic protein-binding endothelial regulator causes insulin resistance. Nat. Commun. 12, 1927 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van Golde, J. M. et al. Impaired collateral recruitment and outward remodeling in experimental diabetes. Diabetes 57, 2818–2823 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Niiyama, H., Huang, N. F., Rollins, M. D. & Cooke, J. P. Murine model of hindlimb ischemia. J. Vis. Exp. https://doi.org/10.3791/1035 (2009).

  27. Yan, J. et al. Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells. J. Vasc. Surg. 50, 1412–1422 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Deng H. et al. Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2105339118 (2021).

  29. Boon, R. A. & Horrevoets, A. J. Key transcriptional regulators of the vasoprotective effects of shear stress. Hamostaseologie 29, 39–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Kelley, R. et al. A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling. J. Cell Biol. 184, 597–609 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Villarreal, G. Jr. et al. Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells. Biochem. Biophys. Res. Commun. 391, 984–989 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Moonen, J. R. et al. KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress. Nat. Commun. 13, 4941 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sissaoui, S. et al. Genomic characterization of endothelial enhancers reveals a multifunctional role for NR2F2 in regulation of arteriovenous gene expression. Circ. Res. 126, 875–888 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ola, R. et al. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat. Commun. 7, 13650 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ruiz, S. et al. Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models. J. Clin. Invest. 130, 942–957 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bidart, M. et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell. Mol. Life Sci. 69, 313–324 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Neuhaus, H., Rosen, V. & Thies, R. S. Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech. Dev. 80, 181–184 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Hazarika, S. et al. Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. Circ. Res. 101, 948–956 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Ola, R. et al. SMAD4 prevents flow induced arteriovenous malformations by inhibiting casein kinase 2. Circulation 138, 2379–2394 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Banerjee, K. et al. SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations. J. Clin. Invest. https://doi.org/10.1172/JCI168352 (2023).

  41. Bernabeu, C., Bayrak-Toydemir, P., McDonald, J. & Letarte, M. Potential second-hits in hereditary hemorrhagic telangiectasia. J. Clin. Med. https://doi.org/10.3390/jcm9113571 (2020).

  42. Korshunov, V. A., Schwartz, S. M. & Berk, B. C. Vascular remodeling: hemodynamic and biochemical mechanisms underlying Glagov’s phenomenon. Arter. Thromb. Vasc. Biol. 27, 1722–1728 (2007).

    Article  CAS  Google Scholar 

  43. Schaper, W. Collateral circulation: past and present. Basic Res. Cardiol. 104, 5–21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Simons, M. & Eichmann, A. Molecular controls of arterial morphogenesis. Circ. Res. 116, 1712–1724 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen, H. et al. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development. Proc. Natl Acad. Sci. USA 110, 11887–11892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fisher, O. S. et al. Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex. Nat. Commun. 6, 7937 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Deng, H. et al. MEKK3–TGFbeta crosstalk regulates inward arterial remodeling. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2112625118 (2021).

  48. Deng, H. & Schwartz, M. A. High fluid shear stress inhibits cytokine-driven Smad2/3 activation in vascular endothelial cells. J. Am. Heart Assoc. 11, e025337 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grant R01 HL135582 (M.A.S.) and American Heart Association career development award 24CDA1268658 (H.D.).

Author information

Authors and Affiliations

  1. Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA

    Hanqiang Deng, Jiasheng Zhang, Divyesh Joshi & Martin A. Schwartz

  2. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Hanqiang Deng, Jiasheng Zhang & Martin A. Schwartz

  3. Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Yewei Wang

  4. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA

    Xinchun Pi

  5. Department of Physiology, Anatomy and Genetics, Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, UK

    Sarah De Val

  6. Department of Cell Biology, Yale School of Medicine, and Department of Biomedical Engineering, Yale School of Engineering, New Haven, CT, USA

    Martin A. Schwartz

Authors
  1. Hanqiang Deng
    View author publications

    Search author on:PubMed Google Scholar

  2. Jiasheng Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yewei Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Divyesh Joshi
    View author publications

    Search author on:PubMed Google Scholar

  5. Xinchun Pi
    View author publications

    Search author on:PubMed Google Scholar

  6. Sarah De Val
    View author publications

    Search author on:PubMed Google Scholar

  7. Martin A. Schwartz
    View author publications

    Search author on:PubMed Google Scholar

Contributions

H.D. performed most of the experiments, analyzed data and prepared figures and the manuscript. J.Z. performed mouse surgery. Y.W. performed RNAseq analysis. D.J. assisted with mice sample collection. X.P. shared the Bmper floxed mice. S.D.V performed ChIP–seq analysis. M.A.S. supervised and supported the project, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Martin A. Schwartz.

Ethics declarations

Competing interests

A patent application (M.A.S. and H.D.) related to this work was filed. All other authors declare no competing interests.

Peer review

Peer review information

Nature Cardiovascular Research thanks Paul Evans, Pedro Geraldes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 KLF2 suppresses Smad1/5 activation under high FSS in HAECs.

(a–c) Human aortic endothelial cells (HAECs) transfected with control or KLF2 siRNA were subjected to FSS at indicated magnitudes for 12 hours. KLF2 KD efficiency was confirmed by Q-PCR (a), n = 3 experiments, data are presented as means ± s.e.m. Cells were fixed and stained for Smad1. Nucleus/Cytoplasm intensity ratio of Smad1 was quantified, n = 60 cells for each group from 3 experiments. (d, e) Immunostaining of phospho-Smad1/5. Nuclear intensity of Smad1/5 was quantified (normalized to siCtrl 3 dyn/cm2 group), n = 60 cells for each group from 3 experiments. Scale bar: 25 μm. Dots represent values from individual cell; center line indicates median (50% percentile); whiskers indicate minimum to maximum; box bounds indicate interquartile range (c, e). Statistics were calculated by two-tailed unpaired t tests (a) or two-way ANOVA with Tukey’s multiple comparison tests (c, e). ns, not significant.

Source data

Extended Data Fig. 2 KLF2 regulates BMPER expression.

HUVECs were transfected with Ctrl (siCtrl) or KLF2 (siKLF2) siRNA for 4 days, total RNA was extracted and subjected to RNAseq, n = 4 samples for each group. (a) Heatmap showing all differentially expressed genes between siCtrl and siKLF2. (b) Volcano plot of log2 fold change against -log10 p-value (siKLF2 versus siCtrl), red showing differentially up-regulated genes (log2 fold change >1; p-value < 0.05), blue showing differentially down-regulated genes (log2 fold change <−1; p-value < 0.05). Genes related to BMP-Smad1/5 pathway are highlighted. (c) Heatmap show expression of genes relevant to the BMP-Smad1/5 pathway. (d) Q-PCR analysis of BMPER and KLF2 expression, with and without KLF2 KD under indicated FSS levels for 24 h, n = 7 experiments, data are presented as means ± s.e.m. Statistics calculated by two-way ANOVA with Sidak’s multiple comparison tests. ns, not significant. (e) Analysis of KLF4 ChIP-seq dataset from endothelial cells in which constitutively active MEK5 (caMEK5) drove induction of KLF4. caMEK5 triggered increased binding of KLF4 to an intronic region within the BMPER gene, correlating with a near-consensus Klf2/Klf4 motif. The KLF4 binding site correlated with other markers associated with active endothelial enhancer regions, including H3K27Ac and ERG binding.

Source data

Extended Data Fig. 3 Smad7 knockdown in HUVECs.

(a–c) HUVECs transfected with control or Smad7 siRNA were subjected to FSS at indicated magnitudes for 12 hours. Smad7 knockdown efficiency was confirmed by Q-PCR (a), n = 3 experiments, data are presented as means ± s.e.m. Cells were fixed and stained for Smad1. Nuclear/Cytoplasm intensity ratio of Smad1 was quantified, n = 60 cells for each group from 3 experiments. (d, e). Immunostaining of phospho-Smad1/5. Nucleus intensity of Smad1/5 was quantified (normalized to siCtrl 3 dyn/cm2 group), n = 60 cells for each group from 3 experiments. Scale bar: 25 μm. Dots represent values from individual cell; center line indicates median (50% percentile); whiskers indicate minimum to maximum; box bounds indicate interquartile range (c, e). Statistics calculated by two-tailed unpaired t tests (a) or two-way ANOVA with Tukey’s multiple comparison tests (c, e). ns, not significant.

Source data

Extended Data Fig. 4 Smad6 knockdown in HUVECs.

(a–c) HUVECs transfected with control or Smad6 siRNA were subjected to FSS at indicated magnitudes for 12 h. Smad6 knockdown efficiency was confirmed by Q-PCR (a), n = 3 experiments, data are presented as means ± s.e.m. Cells were fixed and stained for Smad1. Nucleus/Cytoplasm intensity ratio of Smad1 was quantified, n = 60 cells for each group from 3 experiments. (d, e). Immunostaining of phospo-Smad1/5. Nucleus intensity of Smad1/5 was quantified (normalized to siCtrl 3 dyn/cm2 group), n = 60 cells for each group from 3 experiments, data showing all points from min to max. Scale bar: 25 μm. Dots represent values from individual cell; center line indicates median (50% percentile); whiskers indicate minimum to maximum; box bounds indicate interquartile range (c, e). Statistics calculated by two-tailed unpaired t tests (a) or two-way ANOVA with Tukey’s multiple comparison tests (c, e). ns, not significant.

Source data

Extended Data Fig. 5 BMPER mediates high FSS-induced Smad1/5 suppression in HAECs.

(a–c) Human aortic endothelial cells (HAECs) transfected with control or BMPER siRNA were subjected to FSS at indicated magnitudes for 12 h. BMPER knockdown efficiency was confirmed by western blotting (a). Cells were fixed and stained for Smad1. Nucleus/Cytoplasm intensity ratio of Smad1 was quantified, n = 60 cells for each group from 3 experiments. (d, e). Immunostaining of phospo-Smad1/5. Nucleus intensity of Smad1/5 was quantified (normalized to siCtrl 3 dyn/cm2 group), n = 60 cells for each group from 3 experiments. Scale bar: 25 μm. Dots represent values from individual cell; center line indicates median (50% percentile); whiskers indicate minimum to maximum; box bounds indicate interquartile range (c, e). Statistics calculated by two-way ANOVA with Tukey’s multiple comparison tests (c, e). ns, not significant.

Source data

Extended Data Fig. 6 Clip control and entire cross sections immunostaining for AVF model.

(a, b) H&E staining and quantification of vessel circumference in cross sections from LCA and RCA without anastomosis, n = 6 mice. Scale bar: 100 μm. (c) Immunostaining of KLF4 and CD31 in the entire cross sections of RCA and LCA at day 3. Representative sections were from one out of six mice. Scale bar: 75 μm. (d, e) Higher magnification of KLF4 immunostaining and quantification in the RCA and LCA, n = 6 mice, data are presented as means ± s.e.m. Arrowheads indicate nuclei and KLF4 positive area in artery ECs. Scale bar: 25 μm. ns: not significant, statistics calculated by two-tailed paired t test. (f) Representative immunostaining of BMPER and CD31 in the entire cross sections of RCA and LCA from BMPER iECKO and Control mice. Three mice per group were examined in this experiment. (g) Representative immunostaining of p-Smad1/5 and CD31 in the entire cross sections of RCA and LCA from BMPER iECKO and Control mice. Three mice per group were examined for this purpose. Scale bar: 75 μm.

Source data

Extended Data Fig. 7 Expression of angiogenic factors in BMPER iECKO mice with BMP9/10 Abs treatment.

BMPER iECKO and control mice at 12 weeks were subjected to HLI surgery and injected with BMP9/10 bAbs or IgG (2.5 mg/kg). At day 2 after Abs injection, gastrocnemius muscle in the calf from ligated side was collected and RNA was extracted for Q-PCR. (a) Expression of Vegfa, Vegfc, Pdgfa, Pdgfb, Angpt1 and Angpt2 in BMPER iECKO mice with BMP9/10 bAbs or IgG treatment after HLI surgery, normalized to control mice with IgG, n = 5 mice per group. Data are presented as means ± s.e.m. Statistics calculated by one-way ANOVA with Tukey’s multiple comparison tests. ns, not significant.

Source data

Extended Data Fig. 8 Blood glucose and CD31 immunostaining in T1D.

(a) After fasting for 10 h, blood glucose was measured for vehicle and STZ-treated male (n = 8 per group) and female (n = 10 per group) mice. Data are presented as means ± s.d. Statistics calculated by two-tailed unpaired t test. (b) Representative images and quantification of CD31 staining of calf muscle sections from IgG or BMP9/10 bAb treated T1D mice. Right, unligated; Left, ligated. n = 4 (male) or 5 (female), data are presented as means ± s.e.m. Scale bar: 75 μm. (c) Higher magnification images of CD31 staining of calf muscle sections from IgG or BMP9/10 bAbs treated T1D mice. Four male and five female mice per group were examined for this purpose. Right, unligated; Left, ligated. Scale bar: 25 μm. Statistics calculated by two-way ANOVA with Tukey’s multiple comparison tests. ns, not significant.

Source data

Extended Data Fig. 9 Body weight and blood glucose in T2D.

(a) Body weight was measured before and 8 weeks after HFD for male (n = 10 per group) and female (n = 10 per group) mice, data are presented as means ± s.e.m. (b) After fasting for 10 h, blood glucose was measured before and 8 weeks after HFD for male (n = 10 per group) and female (n = 10 per group) mice, data are presented as means ± s.d. Statistics calculated by two-tailed paired t test.

Source data

Extended Data Fig. 10 Immunostaining in T2D mice after BMP9/10 blocking Abs treatment and pathway diagram.

(a, b) Representative images and quantification of CD31 staining of calf muscle sections from IgG or BMP9/10 bAbs treated T2D mice. Scale bar: 75 μm. (c, d) Representative images and quantification of p-Akt S473 staining of thigh muscle sections from IgG or BMP9/10 bAbs treated T2D mice. (e, f) Representative images and quantification of BMPER staining of thigh muscle sections from IgG or BMP9/10 bAbs treated T2D mice Scale bar: 75 μm. Right, unligated; Left, ligated. n = 5 mice for both male and female, data are presented as means ± s.e.m. Statistics calculated by two-way ANOVA with Sidak’s multiple comparison tests. ns, not significant. (g) Pathway diagram: high FSS suppresses Smad1/5 activation through KLF2-dependent induction of BMPER, which de-represses Akt to enable vessel remodeling.

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2.

Reporting Summary

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 1

Unprocessed western blots.

Source Data Fig. 2

Statistical source data.

Source Data Fig. 2

Unprocessed western blots.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 4

Unprocessed western blots.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 6

Statistical source data.

Source Data Fig. 7

Statistical source data.

Source Data Fig. 8

Statistical source data.

Source Data Extended Data Fig. 1/Table 1

Statistical source data.

Source Data Extended Data Fig. 2/Table 2

Statistical source data.

Source Data Extended Data Fig. 3/Table 3

Statistical source data.

Source Data Extended Data Fig. 4/Table 4

Statistical source data.

Source Data Extended Data Fig. 5/Table 5

Statistical source data.

Source Data Extended Data Fig. 5/Table 5

Unprocessed western blots.

Source Data Extended Data Fig. 6/Table 6

Statistical source data.

Source Data Extended Data Fig. 7/Table 7

Statistical source data.

Source Data Extended Data Fig. 8/Table 8

Statistical source data.

Source Data Extended Data Fig. 9/Table 9

Statistical source data.

Source Data Extended Data Fig. 10/Table 10

Statistical source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, H., Zhang, J., Wang, Y. et al. A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling. Nat Cardiovasc Res 3, 785–798 (2024). https://doi.org/10.1038/s44161-024-00496-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44161-024-00496-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing