Elastin microfibril interface–located protein 1, transforming growth factor beta, and implications on cardiovascular complications

Randell, Amy; Daneshtalab, Noriko

doi:10.1016/j.jash.2017.04.010

Cited by 27 publications

(15 citation statements)

References 77 publications

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“…snail-1 directs epithelial-to-mesenchymal transition (EMT) behaviors (Fuxe et al, 2010), and activates expression of both regenerative ECM components and twist family members, which are expressed in limb blastemal cells (Kragl et al, 2013;Bryant et al, 2017). Moreover, dividing cells highly expressed ECM components such as emilin-1 and fibrillin-2, which modulate TGF-β signaling through interactions with ltbp1 (Neptune et al, 2003;Randell and Daneshtalab, 2017), indicating that both an intra-and extracellular TGF-β signaling network is established. Surprisingly, we observed the strong repression of many growth factor signaling pathways in early regenerating stump tissues.…”

Section: Discussionmentioning

confidence: 99%

Blastemal progenitors modulate immune signaling during early limb regeneration

2019

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Blastema formation, a hallmark of limb regeneration, requires proliferation and migration of progenitors to the amputation plane. Although blastema formation has been well described, the transcriptional programs that drive blastemal progenitors remain unknown. We transcriptionally profiled dividing and non-dividing cells in regenerating stump tissues, as well as the wound epidermis, during early axolotl limb regeneration. Our analysis revealed unique transcriptional signatures of early dividing cells and, unexpectedly, repression of several core developmental signaling pathways in early regenerating stump tissues. We further identify an immunomodulatory role for blastemal progenitors through interleukin 8 (IL-8), a highly expressed cytokine in subpopulations of early blastemal progenitors. Ectopic il-8 expression in nonregenerating limbs induced myeloid cell recruitment, while IL-8 knockdown resulted in defective myeloid cell retention during late wound healing, delaying regeneration. Furthermore, the il-8 receptor cxcr-1/2 was expressed in myeloid cells, and inhibition of CXCR-1/2 signaling during early stages of limb regeneration prevented regeneration. Altogether, our findings suggest that blastemal progenitors are active early mediators of immune support, and identify CXCR-1/2 signaling as an important immunomodulatory pathway during the initiation of regeneration.

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Section: Discussionmentioning

confidence: 99%

Blastemal progenitors modulate immune signaling during early limb regeneration

2019

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“…Fibrillins interact closely with tropoelastin and integrins, and provide a scaffold for elastogenesis in elastic tissues [ 26 ]. Besides, fibrillin-2 interacts directly with fibrillin-1, EMILIN-1, and LTBPs to regulate the bioavailability of TGFβ, a growth factor and key regulator of connective tissue organization and blood vessels development and maintenance [ 27 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

et al. 2018

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Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures.To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER) homeostasis, COLLs folding and extracellular matrix (ECM) organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition into the ECM of several structural proteins crucial to the integrity of soft connective tissues.

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“…128 Elastin microfibril interfacelocated protein 1 (Emilin-1), expressed by PASMCs, is essential for elastogenesis and inhibits TGF-β signaling by binding to its precursor. 129 In nitrofen CDH lungs, Emilin-1 is downregulated. 130 Taken together, these results could suggest an increased autocrine TGF-β signaling in PASMCs, resulting in PASMC proliferation through ALK-1 and increased deposition of collagen.…”

Section: Endothelial Cells Converts Ppet-1 Into Active Et-1mentioning

confidence: 99%

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

2019

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Congenital diaphragmatic hernia (CDH) is a severe birth defect that is characterized by pulmonary hypoplasia and pulmonary hypertension (PHTN). PHTN secondary to CDH is a result of vascular remodeling, a structural alteration in the pulmonary vessel wall that occurs in the fetus. Factors involved in vascular remodeling have been reported in several studies, but their interactions remain unclear. To help understand PHTN pathophysiology and design novel preventative and treatment strategies, we have conducted a systematic review of the literature and comprehensively analyzed all factors and pathways involved in the pathogenesis of pulmonary vascular remodeling secondary to CDH in the nitrofen model. Moreover, we have linked the dysregulated factors with pathways involved in human CDH. Of the 358 full-text articles screened, 75 studies reported factors that play a critical role in vascular remodeling secondary to CDH. Overall, the impairment of epithelial homeostasis present in pulmonary hypoplasia results in altered signaling to endothelial cells, leading to endothelial dysfunction. This causes an impairment of the crosstalk between endothelial cells and pulmonary artery smooth muscle cells, resulting in increased smooth muscle cell proliferation, resistance to apoptosis, and vasoconstriction, which clinically translate into PHTN.

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Elastin microfibril interface–located protein 1, transforming growth factor beta, and implications on cardiovascular complications

Cited by 27 publications

References 77 publications

Blastemal progenitors modulate immune signaling during early limb regeneration

Blastemal progenitors modulate immune signaling during early limb regeneration

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

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