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Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis.

ABSTRACT: In this study, we modeled lymphangiogenesis and vascular angiogenesis in a microdevice using a tissue engineering approach. Lymphatic vessels (LV) and blood vessels (BV) were fabricated by sacrificial molding with seeding human lymphatic endothelial cells and human umbilical vein endothelial cells into molded microchannels (600 ?m diameter). During subsequent perfusion culture, lymphangiogenesis and vascular angiogenesis were induced by addition of phorbol 12-myristate 13-acetate (PMA) and VEGF-C or VEGF-A characterized by podoplanin and Prox-1 expression. The lymphatic capillaries formed button-like junctions treated with dexamethasone. To test the potential for screening anti-angiogenic (vascular and lymphatic) factors, antagonists of VEGF were introduced. We found that an inhibitor of VEGF-R3 did not completely suppress lymphatic angiogenesis with BVs present, although lymphatic angiogenesis was selectively prevented by addition of a VEGF-R3 inhibitor without BVs. To probe the mechanism of action, we focus on matrix metalloproteinase (MMP) secretion by vascular endothelial cells and lymphatic endothelial cells under monoculture or co-culture conditions. We found that vascular angiogenesis facilitated lymphangiogenesis via remodeling of the local microenvironment by the increased secretion of MMP, mainly by endothelial cells. Applications of this model include a drug screening assay for corneal disease and models for tumorigenesis including lymphatic angiogenesis and vascular angiogenesis.

SUBMITTER: Osaki T

PROVIDER: S-EPMC6223658 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis.

Osaki Tatsuya T Serrano Jean C JC Kamm Roger D RD

Regenerative engineering and translational medicine 20180423 3

In this study, we modeled lymphangiogenesis and vascular angiogenesis in a microdevice using a tissue engineering approach. Lymphatic vessels (LV) and blood vessels (BV) were fabricated by sacrificial molding with seeding human lymphatic endothelial cells and human umbilical vein endothelial cells into molded microchannels (600 μm diameter). During subsequent perfusion culture, lymphangiogenesis and vascular angiogenesis were induced by addition of phorbol 12-myristate 13-acetate (PMA) and VEGF- ...[more]

PMID: 30417074

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Project description:BackgroundThe 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.MethodsWe examined angiogenesis and lymphangiogenesis during human pancreas development between 9 and 22 weeks of gestation (W9-W22) by immunohistochemistry.ResultsAs 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.ConclusionOur 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.

Project description:The formation of new blood vessels (angiogenesis) is required for the growth of most tumors. The tumor microenvironment also induces lymphangiogenic factors that promote metastatic spread. Anti-angiogenic therapy targets the mechanisms behind the growth of the tumor vasculature. During the past two decades, several strategies targeting blood and lymphatic vessels in tumors have been developed. The blocking of vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling has proven effective for inhibition of tumor angiogenesis and growth, and inhibitors of VEGF-C/VEGFR-3 involved in lymphangiogenesis have recently entered clinical trials. However, thus far anti-angiogenic treatments have been less effective in humans than predicted on the basis of pre-clinical tests in mice. Intrinsic and induced resistance against anti-angiogenesis occurs in patients, and thus far the clinical benefit of the treatments has been limited to modest improvements in overall survival in selected tumor types. Our current knowledge of tumor angiogenesis is based mainly on experiments performed in tumor-transplanted mice, and it has become evident that these models are not representative of human cancer. For an improved understanding, angiogenesis research needs models that better recapitulate the multistep tumorigenesis of human cancers, from the initial genetic insults in single cells to malignant progression in a proper tissue environment. To improve anti-angiogenic therapies in cancer patients, it is necessary to identify additional molecular targets important for tumor angiogenesis, and to get mechanistic insight into their interactions for eventual combinatorial targeting. The recent development of techniques for manipulating the mammalian genome in a precise and predictable manner has opened up new possibilities for the generation of more reliable models of human cancer that are essential for the testing of new therapeutic strategies. In addition, new imaging modalities that permit visualization of the entire mouse tumor vasculature down to the resolution of single capillaries have been developed in pre-clinical models and will likely benefit clinical imaging.

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Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis.

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Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis.

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