Making Microvascular Networks Work: Angiogenesis, Remodeling, and Pruning

Pries, Axel R.; Secomb, Timothy W.

doi:10.1152/physiol.00012.2014

Cited by 100 publications

(101 citation statements)

References 80 publications

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“…In vascular networks, efficiency is achieved by hierarchical structure and extensive ramification, which together maximize convection and diffusion (Pries and Secomb, 2014). Within these networks, each feeding arteriole gives rise to numerous smaller precapillary arterioles, which in turn drain to venules via even smaller capillary segments.…”

Section: Discussionmentioning

confidence: 99%

Alk1 controls arterial endothelial cell migration in lumenized vessels

Rochon¹,

Menon²,

Roman³

2016

Journal of Cell Science

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Heterozygous loss of the arterial-specific TGFβ type I receptor, activin receptor-like kinase 1 (ALK1; ACVRL1), causes hereditary hemorrhagic telangiectasia (HHT). HHT is characterized by development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). However, how decreased ALK1 signaling leads to AVMs is unknown. To understand the cellular mis-steps that cause AVMs, we assessed endothelial cell behavior in alk1-deficient zebrafish embryos, which develop cranial AVMs. Our data demonstrate that alk1 loss has no effect on arterial endothelial cell proliferation but alters arterial endothelial cell migration within lumenized vessels. In wild-type embryos, alk1-positive cranial arterial endothelial cells generally migrate towards the heart, against the direction of blood flow, with some cells incorporating into endocardium. In alk1-deficient embryos, migration against flow is dampened and migration in the direction of flow is enhanced. Altered migration results in decreased endothelial cell number in arterial segments proximal to the heart and increased endothelial cell number in arterial segments distal to the heart. We speculate that the consequent increase in distal arterial caliber and hemodynamic load precipitates the flow-dependent development of downstream AVMs.

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Section: Discussionmentioning

confidence: 99%

Alk1 controls arterial endothelial cell migration in lumenized vessels

Rochon¹,

Menon²,

Roman³

2016

Journal of Cell Science

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“…The production of a hemodynamically efficient vascular network can occur either by excessive production of blood vessels followed by the pruning of inefficient vessels, or by sprouting of new vessels in hemodynamically efficient locations in the first place. Though vascular networks do overproduce vessels and prune inefficient ones (Pries and Secomb, 2014), this does not negate the possibility of a bias at the site of sprout initiation in perfused vascular networks. It therefore makes physiological sense that the forces created by blood flow could influence the angiogenic process.…”

Section: Introductionmentioning

confidence: 98%

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

2015

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Angiogenesis is tightly controlled by a number of signalling pathways. Although our understanding of the molecular mechanisms involved in angiogenesis has rapidly increased, the role that biomechanical signals play in this process is understudied. We recently developed a technique to simultaneously analyse flow dynamics and vascular remodelling by time-lapse microscopy in the capillary plexus of avian embryos and used this to study the hemodynamic environment present during angiogenic sprouting. We found that sprouts always form from a vessel at lower pressure towards a vessel at higher pressure, and that sprouts form at the location of a shear stress minimum, but avoid locations where two blood streams merge even if this point is at a lower level of shear stress than the sprouting location. Using these parameters, we were able to successfully predict sprout location in quail embryos. We also found that the pressure difference between two vessels is permissive to elongation, and that sprouts will either change direction or regress if the pressure difference becomes negative. Furthermore, the sprout elongation rate is proportional to the pressure difference between the two vessels. Our results show that flow dynamics are predictive of the location of sprout formation in perfused vascular networks and that pressure differences across the interstitium can guide sprout elongation.

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“…Finally, sustained tone influences vascular remodelling, with deep tone being a drive for inward remodelling 23, 24. Previous modelling studies have shown that conducted responses, as important tone regulators, may play a role in vascular structural adaptations 13, 25. Speculatively, conduction of tone could thus result in a smoothing out of irregularities in vascular structure and calibre.…”

Section: Discussionmentioning

confidence: 99%

“…However, coordination of tone is also required at a time scale in the order of minutes to hours. Moreover, modelling studies have shown the importance of conducted responses in structural adaptations in vascular networks13, 14 To the best of our knowledge, only few earlier studies addressed longer lasting stimulation, demonstrating maintenance of conducted vasodilator responses up to two minutes 15, 16. The conduction of vasomotor responses during longer periods has not been studied so far.…”

Section: Introductionmentioning

confidence: 99%

Sustained conduction of vasomotor responses in rat mesenteric arteries in a two‐compartment in vitro set‐up

et al. 2018

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AimConduction of vasomotor responses may contribute to long‐term regulation of resistance artery function and structure. Most previous studies have addressed conduction of vasoactivity only during very brief stimulations. We developed a novel set‐up that allows the local pharmacological stimulation of arteries in vitro for extended periods of time and studied the conduction of vasomotor responses in rat mesenteric arteries under those conditions.MethodsThe new in vitro set‐up was based on the pressure myograph. The superfusion chamber was divided halfway along the vessel into two compartments, allowing an independent superfusion of the arterial segment in each compartment. Local and remote cumulative concentration‐response curves were obtained for a range of vasoactive agents. Additional experiments were performed with the gap junction inhibitor 18β‐glycyrrhetinic acid and in absence of the endothelium.ResultsPhenylephrine‐induced constriction and acetylcholine‐induced dilation were conducted over a measured distance up to 2.84 mm, and this conduction was maintained for 5 minutes. Conduction of acetylcholine‐induced dilation was inhibited by 18β‐glycyrrhetinic acid, and conduction of phenylephrine‐induced constriction was abolished in absence of the endothelium. Constriction in response to high K+ was not conducted. Absence of remote stimulation dampened the local response to phenylephrine.ConclusionThis study demonstrates maintained conduction of vasoactive responses to physiological agonists in rat mesenteric small arteries likely via gap junctions and endothelial cells, providing a possible mechanism for the sustained functional and structural control of arterial networks.

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Making Microvascular Networks Work: Angiogenesis, Remodeling, and Pruning

Cited by 100 publications

References 80 publications

Alk1 controls arterial endothelial cell migration in lumenized vessels

Alk1 controls arterial endothelial cell migration in lumenized vessels

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

Sustained conduction of vasomotor responses in rat mesenteric arteries in a two‐compartment in vitro set‐up

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