Camilla Norrmén

Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis

Lymphatic vessels are essential for the removal of interstitial fluid and prevention of tissue edema. Lymphatic capillaries lack associated mural cells, and collecting lymphatic vessels have valves, which prevent lymph backflow. In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2. We report that Foxc2−/− mice show abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, agenesis of valves and lymphatic dysfunction. In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4). Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process. Our results indicate that an abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects, underlie the pathogenesis of LD.

Transcription Factor PROX1 Induces Colon Cancer Progression by Promoting the Transition from Benign to Highly Dysplastic Phenotype

The Drosophila transcription factor Prospero functions as a tumor suppressor, and it has been suggested that the human counterpart of Prospero, PROX1, acts similarly in human cancers. However, we show here that PROX1 promotes dysplasia in colonic adenomas and colorectal cancer progression. PROX1 expression marks the transition from benign colon adenoma to carcinoma in situ, and its loss inhibits growth of human colorectal tumor xenografts and intestinal adenomas in Apc(min/+) mice, while its transgenic overexpression promotes colorectal tumorigenesis. Furthermore, in intestinal tumors PROX1 is a direct and dose-dependent target of the beta-catenin/TCF signaling pathway, responsible for the neoplastic transformation. Our data underscore the complexity of cancer pathogenesis and implicate PROX1 in malignant tumor progression through the regulation of cell polarity and adhesion.

Molecular mechanisms of lymphatic vascular development

Abstract.Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.

Biological Basis of Therapeutic Lymphangiogenesis

The lymphatic vascular system is crucial for the regulation of tissue fluid homeostasis, immune function, and fat metabolism. Lymphatic dysfunction, either due to gene mutations or secondary to damage to the lymph vessels, may lead to lymphedema, a debilitating condition characterized by chronic tissue edema, impaired immunity, and accumulation of subcutaneous fat. The lymphatic and blood vascular systems function in concert to regulate the tissue fluid homeostasis of the body. The pumping force of the heart generates a hydrostatic pressure, which pushes fluid out of the semipermeable blood capillaries into the interstitial space. Most of the extravasated interstitial fluid and macromolecules are absorbed back by the lymphatic vessels, whereas some reabsorption may also occur in the venules, depending on the tissue (Figure 1).1 Increased endothelial permeability, venous obstruction or insufficiency, and lymphatic vessel dysfunction lead to tissue swelling, or edema (Figure 1). Figure 1. Contributions of the blood and lymphatic vascular systems to tissue fluid homeostasis. A through D , Mechanisms leading to tissue edema.1 Normal fluid homeostasis in tissues is schematically illustrated in A : Colloid proteins and associated water are constantly filtrated from the arterial side of the capillary bed into the interstitial space (red arrows). The majority of the filtrate is collected by the lymphatic capillaries (green arrows); some of the fluid may be reabsorbed into the capillaries on the venous side of the capillary bed (blue arrows). B , Under the conditions of increased blood vascular permeability, such as in inflammation, the amount of filtrate is dramatically increased. Although the lymphatic vessels have a remarkable capacity to increase their drainage, sometimes the system is overwhelmed and net edema remains. C , Obstruction of the veins, for example, due to venous thrombosis or venous insufficiency will impair reabsorption (Reabs) and increase blood pressure within the …

Liprin β1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity

The lymphatic vasculature is important for the regulation of tissue fluid homeostasis, immune response, and lipid absorption, and the development of in vitro models should allow for a better understanding of the mechanisms regulating lymphatic vascular growth, repair, and function. Here we report isolation and characterization of lymphatic endothelial cells from human intestine and show that intestinal lymphatic endothelial cells have a related but distinct gene expression profile from human dermal lymphatic endothelial cells. Furthermore, we identify liprin beta1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, as highly expressed in intestinal lymphatic endothelial cells in vitro and lymphatic vasculature in vivo, and show that it plays an important role in the maintenance of lymphatic vessel integrity in Xenopus tadpoles.

Phosphorylation Regulates FOXC2-Mediated Transcription in Lymphatic Endothelial Cells

ABSTRACT One of the key mechanisms linking cell signaling and control of gene expression is reversible phosphorylation of transcription factors. FOXC2 is a forkhead transcription factor that is mutated in the human vascular disease lymphedema-distichiasis and plays an essential role in lymphatic vascular development. However, the mechanisms regulating FOXC2 transcriptional activity are not well understood. We report here that FOXC2 is phosphorylated on eight evolutionarily conserved proline-directed serine/threonine residues. Loss of phosphorylation at these sites triggers substantial changes in the FOXC2 transcriptional program. Through genome-wide location analysis in lymphatic endothelial cells, we demonstrate that the changes are due to selective inhibition of FOXC2 recruitment to chromatin. The extent of the inhibition varied between individual binding sites, suggesting a novel rheostat-like mechanism by which expression of specific genes can be differentially regulated by FOXC2 phosphorylation. Furthermore, unlike the wild-type protein, the phosphorylation-deficient mutant of FOXC2 failed to induce vascular remodeling in vivo. Collectively, our results point to the pivotal role of phosphorylation in the regulation of FOXC2-mediated transcription in lymphatic endothelial cells and underscore the importance of FOXC2 phosphorylation in vascular development.

Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development

The Claudin-like protein of 24 kDa (CLP24) is a hypoxia-regulated transmembrane protein of unknown function. We show here that clp24 knockdown in Danio rerio and Xenopus laevis results in defective lymphatic development. Targeted disruption of Clp24 in mice led to enlarged lymphatic vessels having an abnormal smooth muscle cell coating. We also show that the Clp24(-/-) phenotype was further aggravated in the Vegfr2(+/LacZ) or Vegfr3(+/LacZ) backgrounds and that CLP24 interacts with vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGFR-3 and attenuates the transcription factor CREB phosphorylation via these receptors. Our results indicate that CLP24 is a novel regulator of VEGFR-2 and VEGFR-3 signaling pathways and of normal lymphatic vessel structure.

Response to Letter Regarding Article, “Biological Basis of Therapeutic Lymphangiogenesis”

We would like to thank Dr Toska for pointing out an inaccuracy pertaining to Figure 1 in our recent review article.1 Indeed, the figure reflects outdated textbook knowledge on the physiology of fluid exchange between the various compartments (arteries, capillaries, veins, lymphatic vessels, and the interstitium). According to current …

FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1

1. 1. Norrmen, 2. et al . 2009. J. Cell Biol. doi:10.1083/jcb.200901104 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft_id%253Dinfo%253Adoi%252F10.1083%252Fjcb.200901104%26rft_id%253Dinfo%253Apmid%252F19398761%26rft.genre%253Darticle%26rft_val_fmt%