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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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Effects of Alk1 mosaic deletion on proliferation and pericyte coverage in retinal ECs. (A) Phospho–histone H3 (PH3) staining of P6 retinas of Cdh5-CreERT2 Alk1iEC:mTmG mice injected with low-dose (5 µg) tamoxifen at P3. Unrecombined ECs (GFP−; Alk1 positive) are shown in light purple, and recombined ECs (GFP+; Alk1 negative) are shown in green. The graph shows quantification of PH3-positive cells at the vascular front and vascular plexus in GFP− and GFP+ cells (number of positive nuclei normalized to EC surface area; n = 6 retinas, Mann–Whitney; **, P < 0.005). (B) NG2 staining of P6 retinas after Alk1 mosaic deletion. Graph shows the percentage of EC surface area covered by NG2-positive cells (n = 6 retinas, Mann–Whitney; *, P < 0.05). Bars, 50 µm. NS, not significant.
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fig4: Effects of Alk1 mosaic deletion on proliferation and pericyte coverage in retinal ECs. (A) Phospho–histone H3 (PH3) staining of P6 retinas of Cdh5-CreERT2 Alk1iEC:mTmG mice injected with low-dose (5 µg) tamoxifen at P3. Unrecombined ECs (GFP−; Alk1 positive) are shown in light purple, and recombined ECs (GFP+; Alk1 negative) are shown in green. The graph shows quantification of PH3-positive cells at the vascular front and vascular plexus in GFP− and GFP+ cells (number of positive nuclei normalized to EC surface area; n = 6 retinas, Mann–Whitney; **, P < 0.005). (B) NG2 staining of P6 retinas after Alk1 mosaic deletion. Graph shows the percentage of EC surface area covered by NG2-positive cells (n = 6 retinas, Mann–Whitney; *, P < 0.05). Bars, 50 µm. NS, not significant.

Mentions: Flow within the physiological range stabilizes blood vessels primarily by inhibiting proliferation (Akimoto et al., 2000) and by inducing recruitment of mural cells (pericytes and smooth muscle cells; Van Gieson et al., 2003). AVMs have been characterized by impaired recruitment of perivascular cells and increased endothelial cell proliferation. To address the contribution of Alk1 signaling to these events, Alk1iEC mice were crossed with mice carrying the mTmG reporter. As a new, more tractable model for HHT, these mice were then injected with a low dose of 5 µg tamoxifen to delete Alk1 at low frequency, generating mosaic blood vessels composed initially of mainly Alk1-positive cells (mCherry) with a small number of Alk1-negative endothelial cells (GFP). Mosaic deletion of Alk1 resulted in the formation of AVMs in the vascular plexus, which were exclusively composed of the GFP-positive cells that lack Alk1 (Fig. 4). In GFP-negative cells, proliferation was markedly decreased in the vascular plexus, but not at the vascular front, consistent with an antiproliferative role of shear stress. Strikingly, proliferation of GFP-positive cells was minimally decreased in plexus, where flow is high (Fig. 4 A). Furthermore, pericyte coverage was significantly decreased in the vascular plexus, where arteriovenous shunts form, but was unaffected in the sprouting front (Fig. 4 B). No differences in pericyte coverage were observed between recombined and unrecombined cells in control mosaic mice (Fig. S2).


Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia
Effects of Alk1 mosaic deletion on proliferation and pericyte coverage in retinal ECs. (A) Phospho–histone H3 (PH3) staining of P6 retinas of Cdh5-CreERT2 Alk1iEC:mTmG mice injected with low-dose (5 µg) tamoxifen at P3. Unrecombined ECs (GFP−; Alk1 positive) are shown in light purple, and recombined ECs (GFP+; Alk1 negative) are shown in green. The graph shows quantification of PH3-positive cells at the vascular front and vascular plexus in GFP− and GFP+ cells (number of positive nuclei normalized to EC surface area; n = 6 retinas, Mann–Whitney; **, P < 0.005). (B) NG2 staining of P6 retinas after Alk1 mosaic deletion. Graph shows the percentage of EC surface area covered by NG2-positive cells (n = 6 retinas, Mann–Whitney; *, P < 0.05). Bars, 50 µm. NS, not significant.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037412&req=5

fig4: Effects of Alk1 mosaic deletion on proliferation and pericyte coverage in retinal ECs. (A) Phospho–histone H3 (PH3) staining of P6 retinas of Cdh5-CreERT2 Alk1iEC:mTmG mice injected with low-dose (5 µg) tamoxifen at P3. Unrecombined ECs (GFP−; Alk1 positive) are shown in light purple, and recombined ECs (GFP+; Alk1 negative) are shown in green. The graph shows quantification of PH3-positive cells at the vascular front and vascular plexus in GFP− and GFP+ cells (number of positive nuclei normalized to EC surface area; n = 6 retinas, Mann–Whitney; **, P < 0.005). (B) NG2 staining of P6 retinas after Alk1 mosaic deletion. Graph shows the percentage of EC surface area covered by NG2-positive cells (n = 6 retinas, Mann–Whitney; *, P < 0.05). Bars, 50 µm. NS, not significant.
Mentions: Flow within the physiological range stabilizes blood vessels primarily by inhibiting proliferation (Akimoto et al., 2000) and by inducing recruitment of mural cells (pericytes and smooth muscle cells; Van Gieson et al., 2003). AVMs have been characterized by impaired recruitment of perivascular cells and increased endothelial cell proliferation. To address the contribution of Alk1 signaling to these events, Alk1iEC mice were crossed with mice carrying the mTmG reporter. As a new, more tractable model for HHT, these mice were then injected with a low dose of 5 µg tamoxifen to delete Alk1 at low frequency, generating mosaic blood vessels composed initially of mainly Alk1-positive cells (mCherry) with a small number of Alk1-negative endothelial cells (GFP). Mosaic deletion of Alk1 resulted in the formation of AVMs in the vascular plexus, which were exclusively composed of the GFP-positive cells that lack Alk1 (Fig. 4). In GFP-negative cells, proliferation was markedly decreased in the vascular plexus, but not at the vascular front, consistent with an antiproliferative role of shear stress. Strikingly, proliferation of GFP-positive cells was minimally decreased in plexus, where flow is high (Fig. 4 A). Furthermore, pericyte coverage was significantly decreased in the vascular plexus, where arteriovenous shunts form, but was unaffected in the sprouting front (Fig. 4 B). No differences in pericyte coverage were observed between recombined and unrecombined cells in control mosaic mice (Fig. S2).

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