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Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity
Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0002-3436-3278
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2017 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 19, p. 3590-3601Article in journal (Refereed) Published
Abstract [en]

Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD , 2017. Vol. 144, no 19, p. 3590-3601
Keywords [en]
Lymphatic vasculature, PDGFB, Contraction, Lymphedema, Morphogenesis, Smooth muscle cell
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-337076DOI: 10.1242/dev.147967ISI: 000412120700018PubMedID: 28851707OAI: oai:DiVA.org:uu-337076DiVA, id: diva2:1179389
Funder
Swedish Research Council, 521-2011-3044Swedish Research Council, 2015-00550Swedish Research Council, 542-2014-3535Swedish Cancer Society, CAN 2014/855Swedish Cancer Society, CAN 2015/0735Knut and Alice Wallenberg Foundation, 2015.0030EU, European Research Council, AdG 294556 BbbarrierEU, European Research Council, ERC-2014-CoG-646849Available from: 2018-02-01 Created: 2018-02-01 Last updated: 2018-08-15Bibliographically approved
In thesis
1. Organ-specific mechanisms of vascular development in the mesentery
Open this publication in new window or tab >>Organ-specific mechanisms of vascular development in the mesentery
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Understanding how the vascular systems are formed has significant clinical importance. General mechanisms underlying vascular development have been extensively studied during the past decades. However, the mechanisms regulating the development and function of the blood and lymphatic vessels in specific organs are poorly understood.

The aim of this thesis was to investigate lymphatic vascular development in the mesentery, which is a fold of peritoneum that attaches the intestine to the abdominal wall, and contains arteries, veins, lymphatic vessels, nerves and lymph nodes. We found that mesenteric lymphatic vessels were formed through lymphvasculogenesis - coalescence of isolated lymphatic endothelial cell (LEC) clusters, rather than by lymphangiogenesis - sprouting from the veins or pre-existing lymphatic vessels. The lymphvasculogenic process was selectively sensitive to inhibition of the vascular endothelial growth factor receptor 3 (VEGFR3)/ phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling pathway. Using genetic lineage tracing, we uncovered that part of the mesenteric lymphatic vasculature was derived from cKit lineage cells likely originating from the blood-forming hemogenic endothelium of major arteries (Paper I). This is in contrast to the previously accepted dogma that all mammalian lymphatic vessels are of venous endothelial origin. By characterizing a mouse mutant lacking the non-venous-derived LEC progenitors we found that an alternative venous source of LECs could however compensate to build a functional mesenteric lymphatic vasculature (Paper IV). We further described in the developing mesentery that a transient loss of venous integrity, characterized by the formation of inter-endothelial cell gaps, was accompanied by extravasation of red blood cells, which were cleared by the developing lymphatic vessels. By studying mice with defective platelet function, we revealed a previously unappreciated role of platelets in maintaining the integrity of the remodeling embryonic blood vasculature and thus preventing excessive blood-filling of lymphatic vessels (Paper III). We also studied the mechanism of vessel maturation into functional lymphatic vessels, which involves smooth muscle cell recruitment. Analysis of mice with LEC-specific deletion of Pdgfb, encoding the platelet derived growth factor B (PDGFB), showed that LEC-autonomous PDGFB was required for the recruitment of smooth muscles cells that in turn control lymphatic vessel size and function (Paper II).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1485
Keywords
Lymphatic vasculature, mesentery, hemogenic endothelium, lymphvasculogenesis, endothelial integrity, platelet, blood-filled lymphatic vessel, morphogenesis and maturation, compensation
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-356488 (URN)978-91-513-0406-9 (ISBN)
Public defence
2018-10-05, Rudbeck Hall, Dag Hammarskjölds v 20, Uppsala, 13:00 (English)
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Available from: 2018-09-10 Created: 2018-08-15 Last updated: 2018-10-02

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Mäe, Maarja AndaloussiZhang, YangOrtsäter, HenrikBetsholtz, ChristerMäkinen, Taija

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