Endothelial cell talin1 is essential for embryonic angiogenesis

Monkley, Susan J.; Kostourou, Vassiliki; Spence, Lorraine; Petrich, Brian G.; Coleman, Stacey J.; Ginsberg, Mark H.; Pritchard, Catrin; Critchley, David R.

doi:10.1016/j.ydbio.2010.11.010

Cited by 60 publications

(68 citation statements)

References 54 publications

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“…Of note, talin inactivation in endothelial cells had been shown to cause severe hemorrhaging in mouse embryos. 31 Taken together, these data suggest that talin and THSD1 interact to tether endothelial cells to the underlying basement membrane (see Supplemental Fig. 1 for a model).…”

Section: Discussionmentioning

confidence: 68%

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Santiago‐Sim

Fang

Hennessy

et al. 2016

Stroke

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Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p<0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

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Section: Discussionmentioning

confidence: 68%

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Santiago‐Sim

Fang

Hennessy

et al. 2016

Stroke

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“…[35][36][37][38] Talin, a cytoplasmic protein that interacts with integrin cytoplasmic tails, is crucial for EC adhesion, and its endothelial-specific ablation results in embryonic lethality caused by adhesion defects during developmental angiogenesis. 39 ECM stiffening promotes tension-induced conformational changes in talin, which then exposes a binding site for vinculin. 40 Recruitment of vinculin to talin subsequently strengthens the integrin-actin connection and supports stiffening of the actin cytoskeleton.…”

Section: Mechanotransduction At the Integrin-cytoskeleton Interfacementioning

confidence: 99%

Between Rho(k) and a Hard Place

Huveneers

Daemen

Hordijk

2015

Circulation Research

154

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Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis. vascular stiffening) and the various external cues that regulate this. In addition, we will discuss the relationship between endothelial contractility and leukocyte extravasation and finally address (future) possibilities to therapeutically target ECs to reduce chronic, stiffness-related, vascular inflammation. Systemic Regulation of Vascular StiffnessArterial stiffness is strongly associated with high blood pressure, as well as with aging, and serves as an independent predictor of human cardiovascular disease. An elevation in arterial stiffness increases systolic blood pressure, thereby promoting cardiac hypertrophy, and decreases the diastolic blood pressure which is a trigger for developing myocardial ischemia. 7 Aortic stiffness also affects the microcirculation and vice versa, microcirculatory changes affect aortic stiffness. Stiffening of the aortic wall leads to increased pulse wave velocity (PWV) and premature reflected waves with elevated systolic and pulsatile central hemodynamic load resulting in microcirculatory damages in peripheral tissues. Conversely, microvasculature remodeling elevates systemic vascular resistance and pulse wave reflection, which stiffens the aortic wall, indicating that the endothelium has both a responsive and a causal role in vascular stiffening. 7 Increased PWV accurately estimates arterial wall stiffness and has recently been included in official hypertension guidelines. PWV values increase with age, and increases in aortic PWV is a g...

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“…Gastrulation defects result in early embryonic lethality of Tln1 global knockout mice while Tln2 knockout mice are viable and fertile although early and severe myopathy in skeletal muscles is observed in the Tln2 knockout which is not prominent in the skeletal muscle specific Tln1 knockout [17], [29]. Platelet or endothelial specific Tln1 deficiency results in severe phenotypes in mouse models [114], [57], [122], [131], although some compensation could be demonstrated by exogenous Tln2 in endothelial cells and upregulated Tln2 expression was observed in undifferentiated embryonic stem cells [83], [179]. The vital role of talin in integrin activation and cell adhesion has been established using multiple model organisms [17], [30], [31], [115] as well as tissue-specific inactivation of the Tln1 gene [108], [114], [122].…”

Section: Talin Expression Structure and Subcellular Distributionmentioning

confidence: 99%

Mechanisms of talin-dependent integrin signaling and crosstalk

Das

Ithychanda

Qin

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

108

103

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Cells undergo dynamic remodeling of the cytoskeleton during adhesion and migration on various extracellular matrix (ECM) substrates in response to physiological and pathological cues. The major mediators of such cellular responses are the heterodimeric adhesion receptors, the integrins. Extracellular or intracellular signals emanating from different signaling cascades cause inside-out signaling of integrins via talin, a cystokeletal protein that links integrins to the actin cytoskeleton. Various integrin subfamilies communicate with each other and growth factor receptors under diverse cellular contexts to facilitate or inhibit various integrin-mediated functions. Since talin is an essential mediator of integrin activation, much of the integrin crosstalk would therefore be influenced by talin. However, despite the existence of an extensive body of knowledge on the role of talin in integrin activation and as a stabilizer of ECM-actin linkage, information on its role in regulating inter-integrin communication is limited. This review will focus on the structure of talin, its regulation of integrin activation and discuss its potential role in integrin crosstalk.

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Endothelial cell talin1 is essential for embryonic angiogenesis

Cited by 60 publications

References 54 publications

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Between Rho(k) and a Hard Place

Mechanisms of talin-dependent integrin signaling and crosstalk

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