Alk1 controls arterial endothelial cell migration in lumenized vessels

Rochon, Elizabeth R.; Menon, Prahlad G.; Roman, Beth L.

doi:10.1242/jcs.195545

Cited by 15 publications

(25 citation statements)

References 18 publications

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“…Previous studies have established that acvrl1 morphants phenocopy acvrl1 mutants; for example, both mutant and morphant embryos exhibit characteristic enlargement of cranial vessels by 36 hpf (Corti et al, 2011;Laux et al, 2013;Rochon et al, 2016). At 36 hpf, we found a comparable number of OFT endocardial cells in uninjected controls and acvrl1 morphants ( Fig.…”

Section: Acvrl1 Promotes Oft Expansion Via Endothelial Addition But supporting

confidence: 68%

“…Prior studies in zebrafish have also determined that cells from the arterial vasculature can migrate into the heart, in a direction opposite to that of blood flow, between 24 and 48 hpf (Rochon et al, 2016). We therefore investigated whether endothelial cells from external sources supply cells to the OFT endocardium between 36 and 51 hpf.…”

Section: Proliferation and Addition Contribute To Oft Endocardial Expmentioning

confidence: 98%

“…Importantly, acvrl1 expression is significantly reduced in tnnt2a mutants, suggesting a potent influence of cardiac function on Acvrl1-mediated endothelial cell behaviors (Corti et al, 2011). Indeed, like tnnt2a morphants, acvrl1 mutants demonstrate reduced endothelial migration toward the heart between 24 hpf and 48 hpf (Rochon et al, 2016).…”

Section: Acvrl1 Promotes Oft Expansion Via Endothelial Addition But mentioning

confidence: 99%

“…Next, since prior studies had shown that cardiac function can promote migration of endothelial cells toward the heart between 24 and 48 hpf (Rochon et al, 2016), we evaluated whether cardiac function also influences endothelial displacement from AA1 into the OFT between 36 and 51 hpf, using photoconversion to label AA1 cells in tnnt2a mutant embryos carrying Tg(kdrl:dendra). In contrast to our observations in wild-type siblings, in which labeled AA1 cells consistently contributed to the OFT endocardium, we rarely found labeled cells in the OFT endocardium of tnnt2a mutants (Figs.…”

Section: Cardiac Function Regulates Both Endocardial Proliferation Anmentioning

confidence: 99%

“…This myocardial morphogenesis is spatiotemporally coordinated with that of the underlying ventricular endocardium, where blood flow instigates proliferation and cellular hypertrophy (Dietrich et al, 2014). In a similar timeframe, flow-induced expression of the TGFβ type I receptor Acvrl1 in arterial vessels facilitates migration of endothelial cells into the heart, resulting in the restriction of the diameter of the distal cranial vessels (Corti et al, 2011;Rochon et al, 2016). Flow-related parameters also activate the calcium channels Trpp2 and Trpv4 to upregulate expression of the transcription factor gene klf2a, which remodels the endocardial lining of the atrioventricular canal in a wnt9b-dependent manner (Galvez-Santisteban et al, 2019;Goddard et al, 2017;Heckel et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract

Sidhwani¹,

Boezio

Yang³

et al. 2019

Preprint

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Physical forces are important participants in the cellular dynamics that shape developing organs. During heart formation, for example, contractility and blood flow generate biomechanical cues that influence patterns of cell behavior. Here, we address the interplay between function and form during the assembly of the cardiac outflow tract (OFT), a crucial connection between the heart and vasculature that develops while circulation is underway. In zebrafish, we find that the OFT expands via accrual of both endocardial and myocardial cells. However, when cardiac function is disrupted, OFT endocardial growth ceases, accompanied by reduced proliferation and reduced addition of cells from adjacent vessels. The TGFβ receptor Acvrl1 is required for addition of endocardial cells, but not for their proliferation, indicating distinct regulation of these essential cell behaviors. Together, our results suggest that cardiac function modulates OFT morphogenesis by triggering endocardial cell accumulation that induces OFT lumen expansion and shapes OFT dimensions.

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Section: Acvrl1 Promotes Oft Expansion Via Endothelial Addition But supporting

confidence: 68%

Section: Proliferation and Addition Contribute To Oft Endocardial Expmentioning

confidence: 98%

Section: Acvrl1 Promotes Oft Expansion Via Endothelial Addition But mentioning

confidence: 99%

Section: Cardiac Function Regulates Both Endocardial Proliferation Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract

Sidhwani¹,

Boezio

Yang³

et al. 2019

Preprint

Self Cite

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Fluid shear stress sensing in vascular homeostasis and remodeling: Towards the development of innovative pharmacological approaches to treat vascular dysfunction

Baeyens

2018

Biochemical Pharmacology

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Blood circulation, facilitating gas exchange and nutrient transportation, is a quintessential feature of life in vertebrates. Any disruption to blood flow, may it be by blockade or traumatic rupture, irrevocably leads to tissue infarction or death. Therefore, it is not surprising that hemostasis and vascular adaptation measures have been evolutionarily selected to mitigate the adverse consequences of altered circulation. Blood vessels can be broadly categorized as arteries, veins, or capillaries, based on their structure, hemodynamics, and gas exchange. However, all of them share one property: they are lined with an epithelial sheet called the endothelium, which typically lies on a basement membrane. This endothelium is the primary interface between the flowing blood and the rest of the body, and it has highly specialized molecular mechanisms to detect and respond to changes in blood perfusion. The purpose of this commentary will be to highlight some of the recent developments in the research on blood flow sensing, vascular remodeling, and homeostasis and to discuss the development of innovative pharmaceutical approaches targeting mechanosensing mechanisms to prolong patient survival and improve quality of life. 1. Introduction: physiology of blood flow sensation and adaptation One of the earliest observations of vascular adaptation in response to changes in hemodynamics was made in the nineteenth century by Thoma and these were further investigated by Chapman and Murray in the chick yolk sac; adequate perfusion was found to determine which premature, non-perfused, and unspecified vessels undergo arterial specification and maturation, while under-perfused vessels remain closed and regress [1-3]. These earlier observations are striking: blood vessels are not merely biological pipes, they are dynamic structures shaped by blood flow itself. This dynamic adaptation is not restrained to the developmental stages of the vasculature, with a transient increase in arterial flow being associated with a transient dilation of the mature arteries under increased flow, through vasorelaxant release [4-8]. Furthermore, a sustained increase in flow, as observed in the muscular arteries of physically trained individuals [9,10] or in the uterine artery during pregnancy [11,12], triggers active remodeling of the concerned arteries by increasing their lumen diameter, improving tissue perfusion. Similarly, hypoperfusion of mature blood vessels, following stenosis for example, leads to the inward remodeling of under-perfused vessels. Interestingly, this inward remodeling could not be linked to an increased contraction of the mural cells as vasorelaxants could not relieve it [13]. This indicates a more profound, structural adaptation of the vessel in response to changes in flow. This was later confirmed after observing that mice lacking matrix metalloproteinases could not undergo successful inward remodeling in response to decreased flow due to the lack of remodeling of the collagen matrix [14,15]. These observations, in various animal m...

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Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology

Ruíz¹,

Chandakkar²,

Zhao³

et al. 2017

Human Molecular Genetics

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Hereditary hemorrhagic telangiectasia (HHT) is a highly debilitating and life-threatening genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in bone morphogenetic protein 9 (BMP9)-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. We interrogated the whole-transcriptome in human umbilical vein ECs (HUVECs) and found that ALK1 signaling inhibition was associated with a specific pro-angiogenic gene expression signature, which included a significant elevation of DLL4 expression. By screening the NIH clinical collections of FDA-approved drugs, we identified tacrolimus (FK-506) as the most potent activator of ALK1 signaling in BMP9-challenged C2C12 reporter cells. In HUVECs, tacrolimus activated Smad1/5/8 and opposed the pro-angiogenic gene expression signature associated with ALK1 loss-of-function, by notably reducing Dll4 expression. In these cells, tacrolimus also inhibited Akt and p38 stimulation by vascular endothelial growth factor, a major driver of angiogenesis. In the BMP9/10-immunodepleted postnatal retina-a mouse model of HHT vascular pathology-tacrolimus activated endothelial Smad1/5/8 and prevented the Dll4 overexpression and hypervascularization associated with this model. Finally, tacrolimus stimulated Smad1/5/8 signaling in C2C12 cells expressing BMP9-unresponsive ALK1 HHT mutants and in HHT patient blood outgrowth ECs. Tacrolimus repurposing has therefore therapeutic potential in HHT.

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Alk1 controls arterial endothelial cell migration in lumenized vessels

Cited by 15 publications

References 18 publications

Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract

Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract

Fluid shear stress sensing in vascular homeostasis and remodeling: Towards the development of innovative pharmacological approaches to treat vascular dysfunction

Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology

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