Dual role for CXCL12 signaling in semilunar valve development

Ridge, Liam A.; Kewbank, Dania; Schütz, Dagmar; Stumm, Ralf; Scambler, Peter; Ivins, Sarah

doi:10.1016/j.celrep.2021.109610

Cited by 10 publications

(18 citation statements)

References 84 publications

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“…Over the past few years, disruption of the CXCL12/CXCR4 pathway has been studied during embryonic development, using genetic models to knock out each respective piece of the axis to examine their effects on cardiac development and more specifically, valvular development ( 10 , 21 – 23 ). Knockouts involving the CXCL12/CXCR4 axis are known to cause ventricular septal defects (VSDs), and developmental disruption of aortic arch, pulmonary artery, and coronary artery in animal models ( 10 , 19 , 21 , 22 , 24 ). CXCL12 null mice also present with malformations and decreased cardiac function ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hyperplasia within the semilunar valve (SLV) has been observed in CXCR4 knockout models, indicating the important role this receptor plays during the endothelial-mesenchymal transition and beyond ( 24 ). However, there has been very little done to analyze the AV function of adult KO mouse models ( 10 , 21 ). To the best of our knowledge, this is the first study that links the deletion of CXCR4 in endothelial cells to the development of hemodynamically stable AVS in a murine model.…”

Section: Discussionmentioning

confidence: 99%

“…CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is a homeostatic chemokine expressed in many cell types throughout the body, especially in the presence of tissue damage ( 1 , 8 – 10 ). Its receptor, CXCR4, is a G-protein coupled receptor expressed on the surface of cell types such as endothelial cells, platelets, neurons, and stem cells ( 9 , 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…Evidence has linked CXCR4 to biological processes such as stem cell recruitment, tissue regeneration, angiogenesis, tumor metastasis, cancer development and progression, CNS disease, and cardiovascular diseases ( 9 , 11 , 13 ). CXCR4 is upregulated under conditions of hypoxia, stress injury, and in damaged vascular tissues ( 10 ). Our previous studies have demonstrated the importance of the CXCL12/CXCR4 axis in myocardial repair ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Role of endothelial CXCR4 in the development of aortic valve stenosis

Winnicki

Gadd²,

Ohanyan³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundCXCL12/CXCR4 signaling is essential in cardiac development and repair, however, its contribution to aortic valve stenosis (AVS) remains unclear. In this study, we tested the role of endothelial CXCR4 on the development of AVS.Materials and methodsWe generated CXCR4 endothelial cell-specific knockout mice (EC CXCR4 KO) by crossing CXCR4fl/fl mice with Tie2-Cre mice to study the role of endothelial cell CXCR4 in AVS. CXCR4fl/fl mice were used as controls. Echocardiography was used to assess the aortic valve and cardiac function. Heart samples containing the aortic valve were stained using Alizarin Red for detection of calcification. Masson’s trichrome staining was used for the detection of fibrosis. The apex of the heart samples was stained with wheat germ agglutinin (WGA) to visualize ventricular hypertrophy.ResultsCompared with the control group, the deletion of CXCR4 in endothelial cells led to significantly increased aortic valve peak velocity and aortic valve peak pressure gradient, with decreased aortic valve area and ejection fraction. EC CXCR4 KO mice also developed cardiac hypertrophy as evidenced by increased diastolic and systolic left ventricle posterior wall thickness (LVPW), cardiac myocyte size, and heart weight (HW) to body weight (BW) ratio. Our data also confirmed increased microcalcifications, interstitial fibrosis, and thickened valvular leaflets of the EC CXCR4 KO mice.ConclusionThe data collected throughout this study suggest the deletion of CXCR4 in endothelial cells is linked to the development of aortic valve stenosis and left ventricular hypertrophy. The statistically significant parameters measured indicate that endothelial cell CXCR4 plays an important role in aortic valve development and function. We have compiled compelling evidence that EC CXCR4 KO mice can be used as a novel model for AVS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of endothelial CXCR4 in the development of aortic valve stenosis

Winnicki

Gadd²,

Ohanyan³

et al. 2022

Front. Cardiovasc. Med.

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“…During this process of leaflet remodelling, the details of which remain unclear, the bulky, primitive valve precursors (cushions and ICVSs) are sculpted into thin fibrous leaflets, connected to the vessel wall by hinges that delineate the sinuses (Figure 3). A number of mouse mutants have been described as having thickened, abnormally shaped (dysplastic) leaflets [for example (41,42,(46)(47)(48)(49)]. The leaflets in these mutants are characterised by having excessive cell numbers and/or abnormalities in the ECM; if this leads to the cushions being pushed against one another, it can result in BAV (42,49).…”

Section: Valve Sculptingmentioning

confidence: 99%

Development of the Human Arterial Valves: Understanding Bicuspid Aortic Valve

Henderson

Eley

Turner

et al. 2022

Front. Cardiovasc. Med.

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Abnormalities in the arterial valves are some of the commonest congenital malformations, with bicuspid aortic valve (BAV) occurring in as many as 2% of the population. Despite this, most of what we understand about the development of the arterial (semilunar; aortic and pulmonary) valves is extrapolated from investigations of the atrioventricular valves in animal models, with surprisingly little specifically known about how the arterial valves develop in mouse, and even less in human. In this review, we summarise what is known about the development of the human arterial valve leaflets, comparing this to the mouse where appropriate.

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Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site

Schraw

Sok

Desrosiers

et al. 2023

Cancer

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BackgroundStudies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.MethodsBirth defect–GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population‐based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial).ResultsBirth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3–2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9–22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3–5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2–3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0–2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1–6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex‐stratified analyses, associations were observed among males but not females.ConclusionsThese data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereas males with nonsyndromic defects and females are not at an increased risk.Plain Language Summary We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

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Dual role for CXCL12 signaling in semilunar valve development

Cited by 10 publications

References 84 publications

Role of endothelial CXCR4 in the development of aortic valve stenosis

Role of endothelial CXCR4 in the development of aortic valve stenosis

Development of the Human Arterial Valves: Understanding Bicuspid Aortic Valve

Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site

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