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Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia

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ABSTRACT

Mutations of the endothelial BMP9/10 receptors Alk1 and endoglin are associated with vascular malformations in hereditary hemorrhagic telangiectasia (HHT). Baeyens et al. report that fluid flow potentiates BMP activation of Alk1 signaling to stabilize blood vessels. HHT lesions thus result from a defect in a synergistic mechanical/biochemical signaling pathway.

No MeSH data available.


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Effect of Alk1 or endoglin depletion on FSS responses. (A) KLF2 and KLF4 message levels by quantitative RT-PCR after flow for 16 h in HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 3, two-way ANOVA; *, P < 0.05; *** or $$$, P < 0.001; **** or $$$$, P < 0.0001). (B) Endothelial cell proliferation in response to 1 ng/ml BMP9 or 12 dynes/cm2 for 24 h after transfection with scrambled, Alk1, or Endoglin siRNA (QIAGEN). Cell proliferation was measured by incorporation of EdU during the last 4 h. (C) HUVECs were stimulated by 1 ng/ml BMP9 or 12 dynes/cm2 for 3 h. Expression of pericyte recruitment genes (PDGF, TGF-β< and jagged1) was assayed by quantitative RT-PCR (n = 4–12, two-way ANOVA; *, P < 0.05; **, P < 0.01; ****, P < 0.0001). (D) Pericyte density in fibrin gels without stimulation or after 96 h of 10 dynes/cm2 flow on HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 4–6 gels from four independent experiments, two-way ANOVA; **, P < 0.01). (E) Distribution of pericytes in fibrin gels, relative to the endothelial monolayer with or without 10 dynes/cm2 flow for 96 h. HUVECs were transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN); n = 5–7 gels from four independent experiments, two-way ANOVA; * or $, P < 0.05; **, P < 0.01; **** or $$$$, P < 0.0001; NS, not significant.
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fig5: Effect of Alk1 or endoglin depletion on FSS responses. (A) KLF2 and KLF4 message levels by quantitative RT-PCR after flow for 16 h in HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 3, two-way ANOVA; *, P < 0.05; *** or $$$, P < 0.001; **** or $$$$, P < 0.0001). (B) Endothelial cell proliferation in response to 1 ng/ml BMP9 or 12 dynes/cm2 for 24 h after transfection with scrambled, Alk1, or Endoglin siRNA (QIAGEN). Cell proliferation was measured by incorporation of EdU during the last 4 h. (C) HUVECs were stimulated by 1 ng/ml BMP9 or 12 dynes/cm2 for 3 h. Expression of pericyte recruitment genes (PDGF, TGF-β< and jagged1) was assayed by quantitative RT-PCR (n = 4–12, two-way ANOVA; *, P < 0.05; **, P < 0.01; ****, P < 0.0001). (D) Pericyte density in fibrin gels without stimulation or after 96 h of 10 dynes/cm2 flow on HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 4–6 gels from four independent experiments, two-way ANOVA; **, P < 0.01). (E) Distribution of pericytes in fibrin gels, relative to the endothelial monolayer with or without 10 dynes/cm2 flow for 96 h. HUVECs were transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN); n = 5–7 gels from four independent experiments, two-way ANOVA; * or $, P < 0.05; **, P < 0.01; **** or $$$$, P < 0.0001; NS, not significant.

Mentions: As controls, we measured levels of Klf2 and Klf4 mRNA (Fig. 5 A), two transcription factors whose expression shows strong, magnitude-dependent induction by FSS in endothelial cells (Dekker et al., 2002; Hamik et al., 2007). Depletion of Alk1 or endoglin moderately increased induction of Klf2 and Klf4 by FSS. This major flow pathway therefore does not require, but instead appears to be partially restrained by, Alk1–endoglin signaling.


Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia
Effect of Alk1 or endoglin depletion on FSS responses. (A) KLF2 and KLF4 message levels by quantitative RT-PCR after flow for 16 h in HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 3, two-way ANOVA; *, P < 0.05; *** or $$$, P < 0.001; **** or $$$$, P < 0.0001). (B) Endothelial cell proliferation in response to 1 ng/ml BMP9 or 12 dynes/cm2 for 24 h after transfection with scrambled, Alk1, or Endoglin siRNA (QIAGEN). Cell proliferation was measured by incorporation of EdU during the last 4 h. (C) HUVECs were stimulated by 1 ng/ml BMP9 or 12 dynes/cm2 for 3 h. Expression of pericyte recruitment genes (PDGF, TGF-β< and jagged1) was assayed by quantitative RT-PCR (n = 4–12, two-way ANOVA; *, P < 0.05; **, P < 0.01; ****, P < 0.0001). (D) Pericyte density in fibrin gels without stimulation or after 96 h of 10 dynes/cm2 flow on HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 4–6 gels from four independent experiments, two-way ANOVA; **, P < 0.01). (E) Distribution of pericytes in fibrin gels, relative to the endothelial monolayer with or without 10 dynes/cm2 flow for 96 h. HUVECs were transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN); n = 5–7 gels from four independent experiments, two-way ANOVA; * or $, P < 0.05; **, P < 0.01; **** or $$$$, P < 0.0001; NS, not significant.
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fig5: Effect of Alk1 or endoglin depletion on FSS responses. (A) KLF2 and KLF4 message levels by quantitative RT-PCR after flow for 16 h in HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 3, two-way ANOVA; *, P < 0.05; *** or $$$, P < 0.001; **** or $$$$, P < 0.0001). (B) Endothelial cell proliferation in response to 1 ng/ml BMP9 or 12 dynes/cm2 for 24 h after transfection with scrambled, Alk1, or Endoglin siRNA (QIAGEN). Cell proliferation was measured by incorporation of EdU during the last 4 h. (C) HUVECs were stimulated by 1 ng/ml BMP9 or 12 dynes/cm2 for 3 h. Expression of pericyte recruitment genes (PDGF, TGF-β< and jagged1) was assayed by quantitative RT-PCR (n = 4–12, two-way ANOVA; *, P < 0.05; **, P < 0.01; ****, P < 0.0001). (D) Pericyte density in fibrin gels without stimulation or after 96 h of 10 dynes/cm2 flow on HUVECs transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN; n = 4–6 gels from four independent experiments, two-way ANOVA; **, P < 0.01). (E) Distribution of pericytes in fibrin gels, relative to the endothelial monolayer with or without 10 dynes/cm2 flow for 96 h. HUVECs were transfected with scrambled, Alk1, or Endoglin siRNA (QIAGEN); n = 5–7 gels from four independent experiments, two-way ANOVA; * or $, P < 0.05; **, P < 0.01; **** or $$$$, P < 0.0001; NS, not significant.
Mentions: As controls, we measured levels of Klf2 and Klf4 mRNA (Fig. 5 A), two transcription factors whose expression shows strong, magnitude-dependent induction by FSS in endothelial cells (Dekker et al., 2002; Hamik et al., 2007). Depletion of Alk1 or endoglin moderately increased induction of Klf2 and Klf4 by FSS. This major flow pathway therefore does not require, but instead appears to be partially restrained by, Alk1–endoglin signaling.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Mutations of the endothelial BMP9/10 receptors Alk1 and endoglin are associated with vascular malformations in hereditary hemorrhagic telangiectasia (HHT). Baeyens et al. report that fluid flow potentiates BMP activation of Alk1 signaling to stabilize blood vessels. HHT lesions thus result from a defect in a synergistic mechanical/biochemical signaling pathway.

No MeSH data available.


Related in: MedlinePlus