Vascular Cell最新文献

{"title":"Therapeutic manipulation of angiogenesis with miR-27b.","authors":"Dorina Veliceasa,&nbsp;Dauren Biyashev,&nbsp;Gangjian Qin,&nbsp;Sol Misener,&nbsp;Alexander Roy Mackie,&nbsp;Raj Kishore,&nbsp;Olga V Volpert","doi":"10.1186/s13221-015-0031-1","DOIUrl":"https://doi.org/10.1186/s13221-015-0031-1","url":null,"abstract":"<p><strong>Background: </strong>Multiple studies demonstrated pro-angiogenic effects of microRNA (miR)-27b. Its targets include Notch ligand Dll4, Sprouty (Spry)-2, PPARγ and Semaphorin (SEMA) 6A. miR-27 effects in the heart are context-dependent: although it is necessary for ventricular maturation, targeted overexpression in cardiomyocytes causes hypertrophy and dysfunction during development. Despite significant recent advances, therapeutic potential of miR-27b in cardiovascular disease and its effects in adult heart remain unexplored. Here, we assessed the therapeutic potential of miR-27b mimics and inhibitors in rodent models of ischemic disease and cancer.</p><p><strong>Methods: </strong>We have used a number of models to demonstrate the effects of miR-27b mimicry and inhibition in vivo, including subcutaneous Matrigel plug assay, mouse models of hind limb ischemia and myocardial infarction and subcutaneous Lewis Lung carcinoma.</p><p><strong>Results: </strong>Using mouse model of myocardial infarction due to the coronary artery ligation, we showed that miR-27b mimic had overall beneficial effects, including increased vascularization, decreased fibrosis and increased ejection fraction. In mouse model of critical limb ischemia, miR-27b mimic also improved tissue re-vascularization and perfusion. In both models, miR-27b mimic clearly decreased macrophage recruitment to the site of hypoxic injury. In contrast, miR-27b increased the recruitment of bone marrow derived cells to the neovasculature, as was shown using mice reconstituted with fluorescence-tagged bone marrow. These effects were due, at least in part, to the decreased expression of Dll4, PPARγ and IL10. In contrast, blocking miR-27b significantly decreased vascularization and reduced growth of subcutaneous tumors and decreased BMDCs recruitment to the tumor vasculature.</p><p><strong>Conclusions: </strong>Our study demonstrates the utility of manipulating miR-27b levels in the treatment of cardiovascular disease and cancer.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-015-0031-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34276371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solenopsin A and analogs exhibit ceramide-like biological activity.","authors":"Isabella Karlsson, Xin Zhou, Raquela Thomas, Allorie T Smith, Michael Y Bonner, Pooja Bakshi, Ajay K Banga, J Phillip Bowen, Ghassan Qabaja, Shavon L Ford, Matthew D Ballard, Kimberly S Petersen, Xuechen Li, Guangping Chen, Besim Ogretmen, Jin Zhang, E Blake Watkins, Rebecca S Arnold, Jack L Arbiser","doi":"10.1186/s13221-015-0030-2","DOIUrl":"10.1186/s13221-015-0030-2","url":null,"abstract":"<p><strong>Background: </strong>(-)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis.</p><p><strong>Methods: </strong>Different analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated.</p><p><strong>Results: </strong>In this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (-)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide.</p><p><strong>Conclusions: </strong>The requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (-)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33337453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased circulating and neutrophil mediated VEGF-A165 release in stable long-term cardiac transplant recipients.","authors":"Damien Vitiello,&nbsp;Diana Chaar,&nbsp;Paul-Eduard Neagoe,&nbsp;Anique Ducharme,&nbsp;Michel Carrier,&nbsp;Guy B Pelletier,&nbsp;Normand Racine,&nbsp;Mark Liszkowski,&nbsp;Martin G Sirois,&nbsp;Michel White","doi":"10.1186/s13221-015-0029-8","DOIUrl":"https://doi.org/10.1186/s13221-015-0029-8","url":null,"abstract":"<p><strong>Background: </strong>Vascular endothelial growth factor (VEGF) may play a role on the allograft remodelling following cardiac transplantation (CTx). We measured the circulating levels of VEGF-A165 concomitantly with the proinflammatory (Interleukin-8; IL-8), anti-inflammatory (IL-1 receptor antagonist; IL-1RA) and their release from neutrophils of CTx recipients.</p><p><strong>Methods: </strong>Eighteen CTx recipients aged 49.6 ± 3.1 years, being transplanted for 145 ± 20 months were age-matched to 35 healthy control (HC) subjects. Concomitantly to plasma assessment, circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-formyl-Met-Leu-Phe (fMLP, 10(-7) M), bacterial lipopolysaccharide (LPS, 1 μg/mL), or tumour necrosis factor alpha (TNF-α, 10 ng/mL).</p><p><strong>Results: </strong>Compared with HC, CTx recipients exhibited a decrease (-80%) in plasmatic levels of VEGF-A165 (225 ± 42 (HC) vs 44 ± 10 pg/mL (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1RA. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a marked decrease ranging from -30 to -88% on their capacity to release VEGF-A165, IL-8 and IL-1RA upon stimulation.</p><p><strong>Conclusions: </strong>Long-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF-A165, as well as neutrophil-mediated release of VEGF-A165, IL-1RA and IL-8 compared to healthy volunteers. The mechanisms and physiological impacts of these findings deserve additional investigations.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-015-0029-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33258023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delta-like 4 mRNA is regulated by adjacent natural antisense transcripts.","authors":"Keguo Li,&nbsp;Tamjid Chowdhury,&nbsp;Padmanabhan Vakeel,&nbsp;Christopher Koceja,&nbsp;Venkatesh Sampath,&nbsp;Ramani Ramchandran","doi":"10.1186/s13221-015-0028-9","DOIUrl":"https://doi.org/10.1186/s13221-015-0028-9","url":null,"abstract":"<p><strong>Background: </strong>Recent evidence suggests that a majority of RNAs in the genome do not code for proteins. They are located in the sense (S) or antisense (AS) orientation and, to date, the functional significance of these non-coding RNAs (ncRNAs) is poorly understood. Here, we examined the relationship between S and AS transcripts in the regulation of a key angiogenesis gene, Delta-like 4 (Dll4).</p><p><strong>Methods: </strong>Rapid Amplification of cDNA Ends (RACE) method was used to identify natural antisense transcripts in the Dll4 gene locus in murine and human endothelial cells, referred to as Dll4 Anti-Sense (Dll4-AS). Messenger RNA (mRNA) levels of Dll4 and Dll4-AS were quantified by real-time PCR. The function of Dll4-AS was investigated by overexpression and knocking down of Dll4-AS.</p><p><strong>Results: </strong>Dll4-AS comprises of three isoforms that map proximal to the Dll4 promoter region. Expression patterns of Dll4-AS isoforms vary among different endothelial cell lines, but are always congruent with those of Dll4. A dual promoter element in the Dll4 locus has been identified that controls the expression of both transcripts. Both Dll4-AS and Dll4 are sensitive to cellular density in that higher cellular density favors their expression. Exogenous Dll4 stimuli such as VEGF, FGF and Notch signaling inhibitor altered both DLL4-AS and DLL4 expression suggesting co-regulation of the transcripts. Also, knocking down of Dll4-AS results in down-regulation of Dll4 expression. As a consequence, endothelial cell proliferation and migration increases in vitro, and sprout formation increases. The regulation of Dll4 by Dll4-AS was also conserved in vivo.</p><p><strong>Conclusion: </strong>A novel form of non-coding RNA-mediated regulation at the Dll4 locus contributes to vascular developmental processes such as cell proliferation, migration and sprouting.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-015-0028-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33254445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"γ-Actin plays a key role in endothelial cell motility and neovessel maintenance.","authors":"Eddy Pasquier,&nbsp;Maria-Pia Tuset,&nbsp;Snega Sinnappan,&nbsp;Michael Carnell,&nbsp;Alexander Macmillan,&nbsp;Maria Kavallaris","doi":"10.1186/s13221-014-0027-2","DOIUrl":"https://doi.org/10.1186/s13221-014-0027-2","url":null,"abstract":"<p><strong>Background: </strong>Angiogenesis plays a crucial role in development, wound healing as well as tumour growth and metastasis. Although the general implication of the cytoskeleton in angiogenesis has been partially unravelled, little is known about the specific role of actin isoforms in this process. Herein, we aimed at deciphering the function of γ-actin in angiogenesis.</p><p><strong>Methods: </strong>Localization of β- and γ-actin in vascular endothelial cells was investigated by co-immunofluorescence staining using monoclonal antibodies, followed by the functional analysis of γ-actin using siRNA. The impact of γ-actin knockdown on the random motility and morphological differentiation of endothelial cells into vascular networks was investigated by timelapse videomicroscopy while the effect on chemotaxis was assessed using modified Boyden chambers. The implication of VE-cadherin, VEGFR-2 and ROCK signalling was then examined by Western blotting and using pharmacological inhibitors.</p><p><strong>Results: </strong>The two main cytoplasmic isoforms of actin strongly co-localized in vascular endothelial cells, albeit with some degree of spatial preference. While β-actin knockdown was not achievable without major cytotoxicity, γ-actin knockdown did not alter the viability of endothelial cells. Timelapse videomicroscopy experiments revealed that γ-actin knockdown cells were able to initiate morphological differentiation into capillary-like tubes but were unable to maintain these structures, which rapidly regressed. This vascular regression was associated with altered regulation of VE-cadherin expression. Interestingly, knocking down γ-actin expression had no effect on endothelial cell adhesion to various substrates but significantly decreased their motility and migration. This anti-migratory effect was associated with an accumulation of thick actin stress fibres, large focal adhesions and increased phosphorylation of myosin regulatory light chain, suggesting activation of the ROCK signalling pathway. Incubation with ROCK inhibitors, H-1152 and Y-27632, completely rescued the motility phenotype induced by γ-actin knockdown but only partially restored the angiogenic potential of endothelial cells.</p><p><strong>Conclusions: </strong>Our study thus demonstrates for the first time that β-actin is essential for endothelial cell survival and γ-actin plays a crucial role in angiogenesis, through both ROCK-dependent and -independent mechanisms. This provides new insights into the role of the actin cytoskeleton in angiogenesis and may open new therapeutic avenues for the treatment of angiogenesis-related disorders.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-014-0027-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33074487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth factor purification and delivery systems (PADS) for therapeutic angiogenesis.","authors":"Eric M George,&nbsp;Huiling Liu,&nbsp;Grant G Robinson,&nbsp;Fakhri Mahdi,&nbsp;Eddie Perkins,&nbsp;Gene L Bidwell","doi":"10.1186/s13221-014-0026-3","DOIUrl":"https://doi.org/10.1186/s13221-014-0026-3","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic angiogenesis with vascular endothelial growth factor (VEGF), delivered either via recombinant protein infusion or via gene therapy, has shown promise in preclinical models of various diseases including myocardial infarction, renovascular disease, preeclampsia, and neurodegenerative disorders. However, dosing, duration of expression, and tissue specificity are challenges to VEGF gene therapy, and recombinant VEGF delivery suffers from extremely rapid plasma clearance, necessitating continuous infusion and/or direct injection at the site of interest.</p><p><strong>Methods: </strong>Here we describe a novel growth factor purification and delivery system (PADS) generated by fusion of VEGF121 to a protein polymer based on Elastin-like Polypeptide (ELP). ELP is a thermally responsive biopolymer derived from a five amino acid repeat sequence found in human tropoelastin. VEGFPADS were constructed by fusion of the ELP coding sequence in-frame with the VEGF121 coding sequence connected by a flexible di-glycine linker. In vitro activity of VEGFPADS was determined using cell proliferation, tube formation, and migration assays with vascular endothelial cells. Pharmacokinetics and biodistribution of VEGFPADS in vivo were compared to free VEGF in mice using quantitative fluorescence techniques.</p><p><strong>Results: </strong>ELP fusion allowed for recombinant expression and simple, non-chromatographic purification of the ELP-VEGF121 chimera in yields as high as 90 mg/L of culture and at very high purity. ELP fusion had no effect on the VEGF activity, as the VEGFPADS were equally potent as free VEGF121 in stimulating HUVEC proliferation, tube formation, and migration. Additionally, the VEGFPADS had a molecular weight five-fold larger than free VEGF121, which lead to slower plasma clearance and an altered biodistribution after systemic delivery in vivo.</p><p><strong>Conclusion: </strong>PADS represent a new method of both purification and in vivo stabilization of recombinant growth factors. The use of this system could permit recombinant growth factors to become viable options for therapeutic angiogenesis in a number of disease models.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-014-0026-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33031450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular biology 2014 in Monterey, California: celebrating 20 years of NAVBO.","authors":"Ian W Tattersal,&nbsp;Henar Cuervo","doi":"10.1186/s13221-014-0025-4","DOIUrl":"https://doi.org/10.1186/s13221-014-0025-4","url":null,"abstract":"<p><p>A meeting report for Vascular Biology 2014, held in Monterey, California and organized by the North American Vascular Biology Organization (NAVBO). </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-014-0025-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33303827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular and molecular basis of Venous insufficiency.","authors":"Elizabeth S Pocock,&nbsp;Tom Alsaigh,&nbsp;Rafi Mazor,&nbsp;Geert W Schmid-Schönbein","doi":"10.1186/s13221-014-0024-5","DOIUrl":"https://doi.org/10.1186/s13221-014-0024-5","url":null,"abstract":"<p><p>Chronic venous disease (CVD) has a range of clinical presentations, including tortuous, distended veins in lower extremities, increasing skin pigmentation, and in severe cases ulceration of the affected skin. Venous insufficiency, a precursor to CVD characterized by improper return of blood from the lower extremities to the heart, must be studied in its earliest stages at a time when preventative measures could be applied in man. This underscores the need for basic research into biomarkers and genetic predisposing factors affecting the progression of venous disease. Investigation over the past decade has yielded insight into these specific genetic, cellular and molecular mechanisms underlying the development of venous disease. Among the many advances include the elucidation of an increasing role for matrix metalloproteinases as important mediators of the degenerative process involved with venous insufficiency. This may be preceded by an inflammatory process which further contributes to venular degeneration and endothelial dysfunction seen in advanced presentation of disease. Furthermore, genomic analyses have shed light upon temporal expression patterns of matrix remodeling proteins in diseased tissue samples. In this review we examine some of the current findings surrounding cellular, molecular and genetic advances in delineating the etiology of chronic venous disease. </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-014-0024-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32917054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of angiogenesis in the pathology of multiple sclerosis.","authors":"Justin Lengfeld,&nbsp;Tyler Cutforth,&nbsp;Dritan Agalliu","doi":"10.1186/s13221-014-0023-6","DOIUrl":"https://doi.org/10.1186/s13221-014-0023-6","url":null,"abstract":"<p><p>Angiogenesis, or the growth of new blood vessels from existing vasculature, is critical for the proper development of many organs. This process is inhibited and tightly regulated in adults, once endothelial cells have acquired organ-specific properties. Within the central nervous system (CNS), angiogenesis and acquisition of blood-brain barrier (BBB) properties by endothelial cells is essential for CNS function. However, the role of angiogenesis in CNS pathologies associated with impaired barrier function remains unclear. Although vessel abnormalities characterized by abnormal barrier function are well documented in multiple sclerosis (MS), a demyelinating disease of the CNS resulting from an immune cell attack on oligodendrocytes, histological analysis of human MS samples has shown that angiogenesis is prevalent in and around the demyelinating plaques. Experiments using an animal model that mimics several features of human MS, Experimental Autoimmune Encephalomyelitis (EAE), have confirmed these human pathological findings and shed new light on the contribution of pre-symptomatic angiogenesis to disease progression. The CNS-infiltrating inflammatory cells that are a hallmark of both MS and EAE secrete several factors that not only contribute to exacerbating the inflammatory process but also promote and stimulate angiogenesis. Moreover, chemical or biological inhibitors that directly or indirectly block angiogenesis provide clinical benefits for disease progression. While the precise mechanism of action for these inhibitors is unknown, preventing pathological angiogenesis during EAE progression holds great promise for developing effective treatment strategies for human MS. </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13221-014-0023-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32878592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lymphangiogenesis and angiogenesis during human fetal pancreas development.","authors":"Matthias S Roost,&nbsp;Liesbeth van Iperen,&nbsp;Ana de Melo Bernardo,&nbsp;Christine L Mummery,&nbsp;Françoise Carlotti,&nbsp;Eelco Jp de Koning,&nbsp;Susana M Chuva de Sousa Lopes","doi":"10.1186/2045-824X-6-22","DOIUrl":"https://doi.org/10.1186/2045-824X-6-22","url":null,"abstract":"<p><strong>Background: </strong>The complex endocrine and exocrine functionality of the human pancreas depends on an efficient fluid transport through the blood and the lymphatic vascular systems. The lymphatic vasculature has key roles in the physiology of the pancreas and in regulating the immune response, both important for developing successful transplantation and cell-replacement therapies to treat diabetes. However, little is known about how the lymphatic and blood systems develop in humans. Here, we investigated the establishment of these two vascular systems in human pancreas organogenesis in order to understand neovascularization in the context of emerging regenerative therapies.</p><p><strong>Methods: </strong>We examined angiogenesis and lymphangiogenesis during human pancreas development between 9 and 22 weeks of gestation (W9-W22) by immunohistochemistry.</p><p><strong>Results: </strong>As early as W9, the peri-pancreatic mesenchyme was populated by CD31-expressing blood vessels as well as LYVE1- and PDPN-expressing lymphatic vessels. The appearance of smooth muscle cell-coated blood vessels in the intra-pancreatic mesenchyme occurred only several weeks later and from W14.5 onwards the islets of Langerhans also became heavily irrigated by blood vessels. In contrast to blood vessels, LYVE1- and PDPN-expressing lymphatic vessels were restricted to the peri-pancreatic mesenchyme until later in development (W14.5-W17), and some of these invading lymphatic vessels contained smooth muscle cells at W17. Interestingly, between W11-W22, most large caliber lymphatic vessels were lined with a characteristic, discontinuous, collagen type IV-rich basement membrane. Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22.</p><p><strong>Conclusion: </strong>Our data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards. Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33141175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}