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1.
Circ Res ; 118(3): 515-30, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26846644

RESUMO

The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Linfangiogênese , Sistema Linfático/fisiopatologia , Linfedema/fisiopatologia , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/imunologia , Sistema Cardiovascular/metabolismo , Humanos , Sistema Linfático/imunologia , Sistema Linfático/metabolismo , Linfedema/imunologia , Linfedema/metabolismo , Transdução de Sinais
2.
J Clin Invest ; 134(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38357924

RESUMO

The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer's disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.


Assuntos
Doença de Alzheimer , Craniossinostoses , Vasos Linfáticos , Camundongos , Animais , Encéfalo , Vasos Linfáticos/patologia , Craniossinostoses/genética , Craniossinostoses/patologia , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Canais Iônicos
3.
J Exp Med ; 214(12): 3645-3667, 2017 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-29141865

RESUMO

The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.


Assuntos
Vasos Linfáticos/fisiologia , Meninges/fisiologia , Animais , Animais Recém-Nascidos , Transporte Biológico/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Dependovirus/metabolismo , Deleção de Genes , Humanos , Indóis/farmacologia , Injeções Intraventriculares , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/efeitos dos fármacos , Masculino , Meninges/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microesferas , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , Sunitinibe , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
J Exp Med ; 212(7): 991-9, 2015 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-26077718

RESUMO

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.


Assuntos
Encéfalo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Líquido Extracelular/metabolismo , Linfonodos/metabolismo , Sistema Linfático/metabolismo , Substâncias Macromoleculares/metabolismo , Análise de Variância , Animais , Encéfalo/anatomia & histologia , Imunofluorescência , Galactosídeos , Proteínas de Fluorescência Verde , Processamento de Imagem Assistida por Computador , Indóis , Sistema Linfático/anatomia & histologia , Camundongos , Camundongos Transgênicos , Microscopia Confocal
5.
J Clin Invest ; 124(3): 878-87, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24590272

RESUMO

Lymphangiogenesis, the growth of lymphatic vessels, is essential in embryonic development. In adults, it is involved in many pathological processes such as lymphedema, inflammatory diseases, and tumor metastasis. Advances during the past decade have dramatically increased the knowledge of the mechanisms of lymphangiogenesis, including the roles of transcription factors, lymphangiogenic growth factors and their receptors, and intercellular and intracellular signaling cascades. Strategies based on these mechanisms are being tested in the treatment of various human diseases such as cancer, lymphedema, and tissue allograft rejection. This Review summarizes the recent progress on lymphangiogenic mechanisms and their applications in disease treatment.


Assuntos
Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/fisiopatologia , Proteínas Angiogênicas/fisiologia , Animais , Antineoplásicos/farmacologia , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Transdução de Sinais
6.
J Clin Invest ; 124(9): 3975-86, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25061878

RESUMO

In glaucoma, aqueous outflow into the Schlemm's canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.


Assuntos
Humor Aquoso/fisiologia , Córnea/irrigação sanguínea , Vasos Linfáticos/fisiologia , Fator C de Crescimento do Endotélio Vascular/fisiologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Movimento Celular , Proliferação de Células , Células Endoteliais/fisiologia , Humanos , Pressão Intraocular , Camundongos , Camundongos Endogâmicos C57BL
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