Endothelial follistatin‐like‐1 regulates the postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling

Tania, Navessa Padma; Maarsingh, Harm; Bos, I. Sophie T.; Mattiotti, Andrea; Prakash, Stuti; Timens, Wim; Gunst, Quinn D.; Jiménez-Borreguero, Luis Jesús; Schmidt, Martina; Hoff, Maurice J.B. van den; Gosens, Reinoud

doi:10.1177/2045893217702340

Cited by 14 publications

(8 citation statements)

References 51 publications

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“…Transthoracic Doppler echocardiography is a noninvasive diagnostic tool for patients with suspected PAH, providing information not only about diagnosis but also about the causes or consequences of PAH . This method has been validated for estimating PAP in PAH patients and in rat and mouse models and is becoming increasingly more relevant in murine models of heart diseases . Using this echocardiography modality, and in accordance with the pulmonary vessel remodeling, we found a reduced PAAT:ET ratio in the pulmonary arteries of 3‐month‐old female PSGL‐1 −/− mice, suggesting that PSGL‐1 −/− mice are susceptible to PH at young age.…”

Section: Discussionmentioning

confidence: 54%

“…Interestingly, Doppler echocardiography is now considered a validated noninvasive method to assess the systolic pressure in the pulmonary artery and right ventricle . The reduction in the ratio of pulmonary artery acceleration time (PAAT) to ejection time (ET) is associated with high PAP in humans and in mice . In the present study, we analyzed the lungs and heart of PSGL‐1 −/− mice, finding pulmonary small vessel remodeling and increased PAP in female mice, and we examined the possible molecular events implicated in this phenotype.…”

Section: Introductionmentioning

confidence: 95%

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Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

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Objective Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and noncurative treatments. As mice deficient in P‐selectin glycoprotein ligand 1 (PSGL‐1) develop a spontaneous SSc‐like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved. Methods Doppler echocardiography was used to estimate pulmonary pressure, immunohistochemistry was used to assess vascular remodeling, and myography of dissected pulmonary artery rings was used to analyze vascular reactivity. Angiotensin II (Ang II) levels were quantified by enzyme‐linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT1R), AT2R, endothelial cell nitric oxide synthase (eNOS), and phosphorylated eNOS expression in lung lysates. Flow cytometry allowed us to determine cytokine production by immune cells and NO production by endothelial cells. In all cases, there were 4–8 mice per experimental group. Results PSGL‐1−/− mice showed lung vessel wall remodeling and a reduced mean ± SD expression of pulmonary AT2R (expression ratio [relative to β‐actin] in female mice age >18 months: wild‐type mice 0.799 ± 0.508 versus knockout mice 0.346 ± 0.229). With aging, female PSGL‐1−/− mice had impaired up‐regulation of estrogen receptor α (ERα) and developed lung vascular endothelial dysfunction coinciding with an increase in mean ± SEM pulmonary Ang II levels (wild‐type 48.70 ± 5.13 pg/gm lung tissue versus knockout 78.02 ± 28.09 pg/gm lung tissue) and a decrease in eNOS phosphorylation, leading to reduced endothelial NO production. These events led to a reduction in the pulmonary artery acceleration time:ejection time ratio in 33% of aged female PSGL‐1−/− mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon‐γ–producing PSGL‐1−/− T cells and B cells and a reduced presence of regulatory T cells. Conclusion The absence of PSGL‐1 induces a reduction in Treg cells, NO production, and ERα expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 95%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

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“…BMPs acquire their activity by binding to Type I and II BMP receptors to form a heterotetrameric complex. The signaling then phosphorylates the Smad proteins and forms complexes with the common mediator Smads, and this directly or indirectly regulates gene transcription, including that of Id genes [ 44 , 45 ]. Human renal proximal tubule epithelial cells use siRNAs to silence Smad expression.…”

Section: Discussionmentioning

confidence: 99%

BMSCs promote the differentiation of NSCs into oligodendrocytes via mediating Id2 and Olig expression through BMP/Smad signaling pathway

et al. 2018

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Neural stem cells (NSCs) have emerged as a promising treatment for spinal cord injuries. However, the increasing expression of bone morphogenetic proteins (BMPs) in spinal cord injury lesion sites seems to have contributed to the limited oligodendroglial differentiation and the majority of the astroglial differentiation of NSCs. In the present study, we demonstrate that BMPs promote NSCs differentiation toward astrocytes and prevent them from differentiating into oligodendrocytes. This effect is accompanied by the increasing expression of Id2 and the reduction in Oilg1/2 expression. Treatment with bone marrow stromal cells (BMSCs) can enhance the development of oligodendrocytes in the presence of BMPs. The analysis of Id2, as well as Olig1 and Olig2 gene expression, reveals that the effect of BMPs on these gene expressions is reversed with the addition of BMSCs. In sum, these data strongly suggest that BMSCs can promote the differentiation of NSCs into oligodendrocytes through mediating Id2 and Olig1/2 expression by blocking the BMP/Smad signaling pathway.

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“…Follistatin family members are multifunctional and essential in tissue restoration and repair and they have been implicated in EC differentiation , angiogenesis , and development of vasculature . However, the role of FSTL3 in these processes is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Follistatin-Like 3 Enhances the Function of Endothelial Cells Derived from Pluripotent Stem Cells by Facilitating β-Catenin Nuclear Translocation Through Inhibition of Glycogen Synthase Kinase-3β Activity

et al. 2018

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The fight against vascular disease requires functional endothelial cells (ECs) which could be provided by differentiation of induced Pluripotent Stem Cells (iPS Cells) in great numbers for use in the clinic. However, the great promise of the generated ECs (iPS‐ECs) in therapy is often restricted due to the challenge in iPS‐ECs preserving their phenotype and function. We identified that Follistatin‐Like 3 (FSTL3) is highly expressed in iPS‐ECs, and, as such, we sought to clarify its possible role in retaining and improving iPS‐ECs function and phenotype, which are crucial in increasing the cells’ potential as a therapeutic tool. We overexpressed FSTL3 in iPS‐ECs and found that FSTL3 could induce and enhance endothelial features by facilitating β‐catenin nuclear translocation through inhibition of glycogen synthase kinase‐3β activity and induction of Endothelin‐1. The angiogenic potential of FSTL3 was also confirmed both in vitro and in vivo. When iPS‐ECs overexpressing FSTL3 were subcutaneously injected in in vivo angiogenic model or intramuscularly injected in a hind limb ischemia NOD.CB17‐Prkdcscid/NcrCrl SCID mice model, FSTL3 significantly induced angiogenesis and blood flow recovery, respectively. This study, for the first time, demonstrates that FSTL3 can greatly enhance the function and maturity of iPS‐ECs. It advances our understanding of iPS‐ECs and identifies a novel pathway that can be applied in cell therapy. These findings could therefore help improve efficiency and generation of therapeutically relevant numbers of ECs for use in patient‐specific cell‐based therapies. In addition, it can be particularly useful toward the treatment of vascular diseases instigated by EC dysfunction. Stem Cells 2018;36:1033–1044

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Endothelial follistatin‐like‐1 regulates the postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling

Cited by 14 publications

References 51 publications

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

BMSCs promote the differentiation of NSCs into oligodendrocytes via mediating Id2 and Olig expression through BMP/Smad signaling pathway

Follistatin-Like 3 Enhances the Function of Endothelial Cells Derived from Pluripotent Stem Cells by Facilitating β-Catenin Nuclear Translocation Through Inhibition of Glycogen Synthase Kinase-3β Activity

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