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Cell-cell interactions influence vascular reprogramming by Prox1 during embryonic development.

ABSTRACT: Lymphangiogenesis is a highly regulated process that involves the reprogramming of venous endothelial cells into early lymphatic endothelial cells. This reprogramming not only displays a polarized expression pattern from the cardinal vein, but also demonstrates vascular specificity; early lymphatics only develop from the cardinal vein and not the related dorsal aorta. In our transgenic model of lymphangiogenesis, we demonstrate that Prox1 overexpression has the ability to reprogram venous endothelium but not early arterial endothelial cells in vivo, in spite of the fact that Prox1 expression is forced onto both vascular beds. Our observations suggest that this specificity during embryogenesis may be due to cell-cell interactions between the developing arterial endothelial cells and smooth muscle cells. These conclusions have far reaching implications on how we understand the vascular specificity of lymphangiogenesis.

SUBMITTER: Kim H

PROVIDER: S-EPMC3544876 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Cell-cell interactions influence vascular reprogramming by Prox1 during embryonic development.

Kim Harold H Cruz Maribelle M Bourdeau Annie A Dumont Daniel J DJ

PloS one 20130114 1

Lymphangiogenesis is a highly regulated process that involves the reprogramming of venous endothelial cells into early lymphatic endothelial cells. This reprogramming not only displays a polarized expression pattern from the cardinal vein, but also demonstrates vascular specificity; early lymphatics only develop from the cardinal vein and not the related dorsal aorta. In our transgenic model of lymphangiogenesis, we demonstrate that Prox1 overexpression has the ability to reprogram venous endoth ...[more]

PMID: 23341894

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Embryonic vascular endothelial cells are malleable to reprogramming via Prox1 to a lymphatic gene signature.

Project description:BackgroundIn vivo studies demonstrate that the Prox1 transcription factor plays a critical role in the development of the early lymphatic system. Upon Prox1 expression, early lymphatic endothelial cells differentiate from the cardinal vein and begin to express lymphatic markers such as VEGFR-3, LYVE-1 and Podoplanin. Subsequent in vitro studies have found that differentiated vascular endothelial cells can be reprogrammed by Prox1 to express a lymphatic gene profile, suggesting that Prox1 can initiate the expression of a unique gene signature during lymphangiogenesis. While the in vitro data suggest that gene reprogramming occurs upon Prox1 expression, it is not clear if this is a direct result of Prox1 in vascular endothelial cells in vivo.ResultsOverexpression of Prox1 in vascular endothelial cells during embryonic development results in the reprogramming of genes to that of a more lymphatic signature. Consequent to this overexpression, embryos suffer from gross edema that results in embryonic lethality at E13.5. Furthermore, hemorrhaging and anemia is apparent along with clear defects in lymph sac development. Alterations in junctional proteins resulting in an increase in vascular permeability upon Prox1 overexpression may contribute to the complications found during embryonic development.ConclusionWe present a novel mouse model that addresses the importance of Prox1 in early embryonic lymphangiogenesis. It is clear that there needs to be a measured pattern of expression of Prox1 during embryonic development. Furthermore, Prox1 reprograms vascular endothelial cells in vivo by creating a molecular signature to that of a lymphatic endothelial cell.

| S-EPMC2909156 | biostudies-literature

Time-Series Interactions of Gene Expression, Vascular Growth and Hemodynamics during Early Embryonic Arterial Development.

Project description:The role of hemodynamic forces within the embryo as biomechanical regulators for cardiovascular morphogenesis, growth, and remodeling is well supported through the experimental studies. Furthermore, clinical experience suggests that perturbed flow disrupts the normal vascular growth process as one etiology for congenital heart diseases (CHD) and for fetal adaptation to CHD. However, the relationships between hemodynamics, gene expression and embryonic vascular growth are poorly defined due to the lack of concurrent, sequential in vivo data. In this study, a long-term, time-lapse optical coherence tomography (OCT) imaging campaign was conducted to acquire simultaneous blood velocity, pulsatile micro-pressure and morphometric data for 3 consecutive early embryonic stages in the chick embryo. In conjunction with the in vivo growth and hemodynamics data, in vitro reverse transcription polymerase chain reaction (RT-PCR) analysis was performed to track changes in transcript expression relevant to histogenesis and remodeling of the embryonic arterial wall. Our non-invasive extended OCT imaging technique for the microstructural data showed continuous vessel growth. OCT data coupled with the PIV technique revealed significant but intermitted increases in wall shear stress (WSS) between first and second assigned stages and a noticeable decrease afterwards. Growth rate, however, did not vary significantly throughout the embryonic period. Among all the genes studied, only the MMP-2 and CASP-3 expression levels remained unchanged during the time course. Concurrent relationships were obtained among the transcriptional modulation of the genes, vascular growth and hemodynamics-related changes. Further studies are indicated to determine cause and effect relationships and reversibility between mechanical and molecular regulation of vasculogenesis.

| S-EPMC4994943 | biostudies-literature

Kaposin-B enhances the PROX1 mRNA stability during lymphatic reprogramming of vascular endothelial cells by Kaposi's sarcoma herpes virus.

Project description:Kaposi's sarcoma (KS) is the most common cancer among HIV-positive patients. Histogenetic origin of KS has long been elusive due to a mixed expression of both blood and lymphatic endothelial markers in KS tumor cells. However, we and others discovered that Kaposi's sarcoma herpes virus (KSHV) induces lymphatic reprogramming of blood vascular endothelial cells by upregulating PROX1, which functions as the master regulator for lymphatic endothelial differentiation. Here, we demonstrate that the KSHV latent gene kaposin-B enhances the PROX1 mRNA stability and plays an important role in KSHV-mediated PROX1 upregulation. We found that PROX1 mRNA contains a canonical AU-rich element (ARE) in its 3'-untranslated region that promotes PROX1 mRNA turnover and that kaposin-B stimulates cytoplasmic accumulation of the ARE-binding protein HuR through activation of the p38/MK2 pathway. Moreover, HuR binds to and stabilizes PROX1 mRNA through its ARE and is necessary for KSHV-mediated PROX1 mRNA stabilization. Together, our study demonstrates that kaposin-B plays a key role in PROX1 upregulation during lymphatic reprogramming of blood vascular endothelial cells by KSHV.

| S-EPMC2921153 | biostudies-literature

HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development.

Project description:Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.

| S-EPMC6045644 | biostudies-literature

DNA methylation reprogramming of functional elements during mammalian embryonic development.

Project description:DNA methylation plays important roles during development. However, the DNA methylation reprogramming of functional elements has not been fully investigated during mammalian embryonic development. Herein, using our modified MethylC-Seq library generation method and published post-bisulphite adapter-tagging (PBAT) method, we generated genome-wide DNA methylomes of human gametes and early embryos at single-base resolution and compared them with mouse methylomes. We showed that the dynamics of DNA methylation in functional elements are conserved between humans and mice during early embryogenesis, except for satellite repeats. We further found that oocyte-specific hypomethylated promoters usually exhibit low CpG densities. Genes with oocyte-specific hypomethylated promoters generally show oocyte-specific hypomethylated genic and intergenic regions, and these hypomethylated regions contribute to the hypomethylation pattern of mammalian oocytes. Furthermore, hypomethylated genic regions with low CG densities correlate with gene silencing in oocytes, whereas hypomethylated genic regions with high CG densities correspond to high gene expression. We further show that methylation reprogramming of enhancers during early embryogenesis is highly associated with the development of almost all human organs. Our data support the hypothesis that DNA methylation plays important roles during mammalian development.

| S-EPMC6079081 | biostudies-literature

Specific Temporal Requirement of Prox1 Activity During Pancreatic Acinar Cell Development.

Project description:Background and aimsAn interactive regulatory network assembled through the induction and downregulation of distinct transcription factors governs acinar cell maturation. Understanding how this network is built is relevant for protocols of directed pancreatic acinar differentiation. The murine transcription factor Prox1 is highly expressed in multipotent pancreatic progenitors and in various mature pancreatic cell types except for acinar cells. In this study, we investigated when is Prox1 expression terminated in developing acinar cells and the potential involvement of its activity in acinar cell specification/differentiation. We also investigated the effects of sustained Prox1 expression in acinar maturation and maintenance.MethodsProx1 acinar expression was analyzed by immunofluorescence and confocal microscopy. Prox1-null embryos (Prox1GFPCre/Δ), Prox1AcOE transgenic mice, histologic and immunostaining methods, transmission electron microscopy, functional assays, and quantitative RNA and RNA-sequencing methods were used to investigate the effects of Prox1 functional deficiency and sustained Prox1 expression in acinar maturation and homeostasis.ResultsImmunostaining results reveal transient Prox1 expression in newly committed embryonic acinar cells. RNA-sequencing demonstrate precocious expression of multiple "late" acinar genes in the pancreas of Prox1GFPCre/Δ embryos. Prox1AcOE transgenic mice carrying sustained Prox1 acinar expression have relatively normal pancreas development. In contrast, Prox1AcOE adult mice have severe pancreatic alterations involving reduced acinar gene expression, abnormal acinar secretory granules, acinar atrophy, increased endoplasmic reticulum stress, and mild chronic inflammation.ConclusionProx1 transient expression in early acinar cells is necessary for correct sequential gene expression. Prox1 expression is terminated in developing acinar cells to complete maturation and to preserve homeostasis.

| S-EPMC10569262 | biostudies-literature

Expression of Prox1 during mouse cochlear development.

Project description:We carried out an analysis of the expression of Prox1, a homeo-domain transcription factor, during mouse inner ear development with particular emphasis on the auditory system. Prox1 is expressed in the otocyst beginning at embryonic day (E)11, in the developing vestibular sensory patches. Expression is down regulated in maturing (myosin VIIA immunoreactive) vestibular hair cells and subsequently in the underlying support cell layer by E16.5. In the auditory sensory epithelium, Prox1 is initially expressed at embryonic day 14.5 in a narrow stripe of cells at the base of the cochlea. This stripe encompasses the full thickness of the sensory epithelium, including developing hair cells and support cells. Over the next several days the stripe of expression extends to the apex, and as the sensory epithelium differentiates Prox1 becomes restricted to a subset of support cells. Double labeling for Prox1 and cell-type-specific markers revealed that the outer hair cells transiently express Prox1. After E18, Prox1 protein is no longer detectable in hair cells, but it continues to be expressed in support cells for the rest of embryogenesis and into the second postnatal week. During this time, Prox1 is not expressed in all support cell types in the organ of Corti, but is restricted to developing Deiters' and pillar cells. The expression is maintained in these cells into the second week of postnatal life, at which time Prox1 is dynamically down regulated. These studies form a baseline from which we can analyze the role of Prox1 in vertebrate sensory development.

| S-EPMC2572724 | biostudies-literature

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| S-EPMC3553377 | biostudies-other

Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation.

Project description:Interactions between platelets, leukocytes, and activated endothelial cells are important during microvascular occlusion; however, the regulatory mechanisms of these heterotypic cell-cell interactions remain unclear. Here, using intravital microscopy to evaluate mice lacking specific isoforms of the serine/threonine kinase AKT and bone marrow chimeras, we found that hematopoietic cell-associated AKT2 is important for neutrophil adhesion and crawling and neutrophil-platelet interactions on activated endothelial cells during TNF-?-induced venular inflammation. Studies with an AKT2-specific inhibitor and cells isolated from WT and Akt KO mice revealed that platelet- and neutrophil-associated AKT2 regulates heterotypic neutrophil-platelet aggregation under shear conditions. In particular, neutrophil AKT2 was critical for membrane translocation of ?M?2 integrin, ?2-talin1 interaction, and intracellular Ca2+ mobilization. We found that the basal phosphorylation levels of AKT isoforms were markedly increased in neutrophils and platelets isolated from patients with sickle cell disease (SCD), an inherited hematological disorder associated with vascular inflammation and occlusion. AKT2 inhibition reduced heterotypic aggregation of neutrophils and platelets isolated from SCD patients and diminished neutrophil adhesion and neutrophil-platelet aggregation in SCD mice, thereby improving blood flow rates. Our results provide evidence that neutrophil AKT2 regulates ?M?2 integrin function and suggest that AKT2 is important for neutrophil recruitment and neutrophil-platelet interactions under thromboinflammatory conditions such as SCD.

| S-EPMC3973084 | biostudies-other

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