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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 blood flow on the development of retinal AVMs under impaired Alk1 signaling. (A) Representative images of P5 retinas stained with isolectin B4 to identify blood vessels in control (Alk1l/l) and Alk1iEC (Cdh5-CreERT2-Alk1iEC) mice after 50 µg tamoxifen injection at P3. (B) Quantification of the number of AVMs in the proximal (<500 µm from the optic nerve) versus distal (>500 µm from the optic nerve) regions of the retina (n = 5). (C) Quantification of the number of branch points in Alk1l/l and Cdh5-CreERT2 (Alk1iEC) mice in the proximal versus distal regions (n = 5, Mann–Whitney; **, P < 0.005). (D) Representative images of P5 retinal vessels from pups injected at P3 with control or BMP9/BMP10 blocking antibodies. v, vein; a, artery. (E and F) Quantification of the number of AVMs (E) or branch points (F) in the proximal and distal regions in mice injected with control or BMP9/BMP10 blocking antibodies (n = 5, Mann–Whitney; *, P < 0.05). Bars, 150 µm. NS, not significant. Error bars represent SEM.
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fig1: Effects of blood flow on the development of retinal AVMs under impaired Alk1 signaling. (A) Representative images of P5 retinas stained with isolectin B4 to identify blood vessels in control (Alk1l/l) and Alk1iEC (Cdh5-CreERT2-Alk1iEC) mice after 50 µg tamoxifen injection at P3. (B) Quantification of the number of AVMs in the proximal (<500 µm from the optic nerve) versus distal (>500 µm from the optic nerve) regions of the retina (n = 5). (C) Quantification of the number of branch points in Alk1l/l and Cdh5-CreERT2 (Alk1iEC) mice in the proximal versus distal regions (n = 5, Mann–Whitney; **, P < 0.005). (D) Representative images of P5 retinal vessels from pups injected at P3 with control or BMP9/BMP10 blocking antibodies. v, vein; a, artery. (E and F) Quantification of the number of AVMs (E) or branch points (F) in the proximal and distal regions in mice injected with control or BMP9/BMP10 blocking antibodies (n = 5, Mann–Whitney; *, P < 0.05). Bars, 150 µm. NS, not significant. Error bars represent SEM.

Mentions: The retinal vasculature develops after birth with the sprouting of a vascular network that starts at the optic nerve and progressively covers the whole retina. The network quickly differentiates into mature arteries and veins interconnected by a capillary network. Computational analysis of blood velocities and shear stress distribution within this developing network revealed a gradient with high shear stress close to the optic nerve and decreasing toward the sprouting front (Bernabeu et al., 2014). To determine whether blood flow plays a role in AVM development in response to impaired Alk1 signaling, we induced endothelial Alk1 deletion during postnatal retinal angiogenesis by crossing Alk1l/l and Cdh5-CreERT2 mice (Alk1iEC; Aspalter et al., 2015). When Alk1 was deleted at postnatal day 3 (P3), it produced arteriovenous shunts by day 5 (Fig. 1 A), similar to the observations of Tual-Chalot et al. (2014). Interestingly, we observed that the shunts were only formed close to the optic nerve, within the better-differentiated vascular plexus, where blood flow was high (Fig. 1 B). In the sprouting front, where blood flow is lower, we instead observed increased branching and hypersprouting, which was never observed in the well-perfused vascular plexus (Fig. 1, A and C). A similar phenotype was observed after intraperitoneal injection of blocking antibodies against BMP9 and BMP10 at P3 (Fig. 1, D–F). When AVM formation was initiated in adult mice by Alk1 deletion and wounding, AVMs were also associated with regions of high blood flow velocity (Park et al., 2009). Thus, impaired Alk1 signaling results in the formation of vascular shunts specifically in regions of high blood flow.


Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia
Effects of blood flow on the development of retinal AVMs under impaired Alk1 signaling. (A) Representative images of P5 retinas stained with isolectin B4 to identify blood vessels in control (Alk1l/l) and Alk1iEC (Cdh5-CreERT2-Alk1iEC) mice after 50 µg tamoxifen injection at P3. (B) Quantification of the number of AVMs in the proximal (<500 µm from the optic nerve) versus distal (>500 µm from the optic nerve) regions of the retina (n = 5). (C) Quantification of the number of branch points in Alk1l/l and Cdh5-CreERT2 (Alk1iEC) mice in the proximal versus distal regions (n = 5, Mann–Whitney; **, P < 0.005). (D) Representative images of P5 retinal vessels from pups injected at P3 with control or BMP9/BMP10 blocking antibodies. v, vein; a, artery. (E and F) Quantification of the number of AVMs (E) or branch points (F) in the proximal and distal regions in mice injected with control or BMP9/BMP10 blocking antibodies (n = 5, Mann–Whitney; *, P < 0.05). Bars, 150 µm. NS, not significant. Error bars represent SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig1: Effects of blood flow on the development of retinal AVMs under impaired Alk1 signaling. (A) Representative images of P5 retinas stained with isolectin B4 to identify blood vessels in control (Alk1l/l) and Alk1iEC (Cdh5-CreERT2-Alk1iEC) mice after 50 µg tamoxifen injection at P3. (B) Quantification of the number of AVMs in the proximal (<500 µm from the optic nerve) versus distal (>500 µm from the optic nerve) regions of the retina (n = 5). (C) Quantification of the number of branch points in Alk1l/l and Cdh5-CreERT2 (Alk1iEC) mice in the proximal versus distal regions (n = 5, Mann–Whitney; **, P < 0.005). (D) Representative images of P5 retinal vessels from pups injected at P3 with control or BMP9/BMP10 blocking antibodies. v, vein; a, artery. (E and F) Quantification of the number of AVMs (E) or branch points (F) in the proximal and distal regions in mice injected with control or BMP9/BMP10 blocking antibodies (n = 5, Mann–Whitney; *, P < 0.05). Bars, 150 µm. NS, not significant. Error bars represent SEM.
Mentions: The retinal vasculature develops after birth with the sprouting of a vascular network that starts at the optic nerve and progressively covers the whole retina. The network quickly differentiates into mature arteries and veins interconnected by a capillary network. Computational analysis of blood velocities and shear stress distribution within this developing network revealed a gradient with high shear stress close to the optic nerve and decreasing toward the sprouting front (Bernabeu et al., 2014). To determine whether blood flow plays a role in AVM development in response to impaired Alk1 signaling, we induced endothelial Alk1 deletion during postnatal retinal angiogenesis by crossing Alk1l/l and Cdh5-CreERT2 mice (Alk1iEC; Aspalter et al., 2015). When Alk1 was deleted at postnatal day 3 (P3), it produced arteriovenous shunts by day 5 (Fig. 1 A), similar to the observations of Tual-Chalot et al. (2014). Interestingly, we observed that the shunts were only formed close to the optic nerve, within the better-differentiated vascular plexus, where blood flow was high (Fig. 1 B). In the sprouting front, where blood flow is lower, we instead observed increased branching and hypersprouting, which was never observed in the well-perfused vascular plexus (Fig. 1, A and C). A similar phenotype was observed after intraperitoneal injection of blocking antibodies against BMP9 and BMP10 at P3 (Fig. 1, D–F). When AVM formation was initiated in adult mice by Alk1 deletion and wounding, AVMs were also associated with regions of high blood flow velocity (Park et al., 2009). Thus, impaired Alk1 signaling results in the formation of vascular shunts specifically in regions of high blood flow.

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