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The Role of Paladin in Endothelial Cell Signaling and Angiogenesis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Mats Hellström)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis, the formation of new blood vessels from a pre-existing vasculature, is crucial during development and for many diseases including cancer. Despite tremendous progress in the understanding of the angiogenic process, many aspects are still not fully elucidated. Several attempts have been made to identify novel genes involved in endothelial cell biology and angiogenesis. Here we focused on Pald1, a recently identified, vascular-enriched gene encoding paladin. Our in vitro studies indicate that paladin is a lipid phosphatase catalyzing dephosphorylation of phosphatidylinositol phosphates, a process essential for endocytosis and intracellular vesicle trafficking.

We confirmed paladin’s vascular expression pattern and revealed a shift from a broad endothelial cell expression during development to an arterial mural cell-restricted expression in several vascular beds in adult mice. Paladin expression in the lung, however, was not restricted to the vasculature, but was also observed in pneumocytes and myofibroblasts. Lungs of female, but not male, Pald1 null mice displayed an obstructive lung phenotype with increased alveolar air sacs that were already apparent early in the alveolarization process. Only endothelial cells, but not other main lung cell types, were affected by loss of paladin. Endothelial cell number was reduced in 4-week old mice, possibly due to increased endothelial turnover in Pald1 deficient lungs.

Vascular defects were also found in the retina. Loss of paladin led to reduced retinal vascular outgrowth accompanied by a hyperdense and hypersprouting vascular front. Downstream signaling of the major angiogenic driver, vascular endothelial growth factor receptor 2 (VEGFR2) was sustained in Pald1 null mice, and VEGFR2 degradation was impaired. Furthermore, paladin inhibited endothelial cell junction stability and loss of paladin led to reduced vascular permeability.

Whether the differences in VEGFR2 signaling and adherens junction stability are connected remains to be fully explored. The newly identified lipid phosphatase activity of paladin and its specific effects on VEGFR2 signaling and adherens junction stability indicate that paladin may be controlling the endocytic pathway.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 47 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1225
Keyword [en]
Pald1, endothelium, lung, vascular permeability, phosphatase, angiogenesis
National Category
Cell and Molecular Biology
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-281708ISBN: 978-91-554-9578-7 (print)OAI: oai:DiVA.org:uu-281708DiVA: diva2:920689
Public defence
2016-06-09, Rudbecksalen (C11), Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-05-19 Created: 2016-03-29 Last updated: 2016-06-01
List of papers
1. Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development
Open this publication in new window or tab >>Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development
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2012 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 241, no 4, 770-786 p.Article in journal (Refereed) Published
Abstract [en]

Background: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains.

Results: We present a mouse knockout allele for Paladin with a beta-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas.

Conclusions: Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.

Keyword
endothelium, angiogenesis, protein phosphatase, KIAA1274, X99384, paladin, LacZ reporter, endothelial cell, smooth muscle cell, brain tumor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-172028 (URN)10.1002/dvdy.23753 (DOI)000301347000011 ()
Available from: 2012-04-02 Created: 2012-04-01 Last updated: 2017-12-07Bibliographically approved
2. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
Open this publication in new window or tab >>Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-281704 (URN)
Available from: 2016-04-18 Created: 2016-03-29 Last updated: 2016-05-24
3. Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeability
Open this publication in new window or tab >>Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeability
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-281706 (URN)
Available from: 2016-04-18 Created: 2016-03-29 Last updated: 2016-05-24

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Nitzsche, Anja

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