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Organ-specific mechanisms of vascular development in the mesentery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. (Taija Mäkinen)ORCID iD: 0000-0002-3436-3278
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 [en]
Lymphatic vasculature, mesentery, hemogenic endothelium, lymphvasculogenesis, endothelial integrity, platelet, blood-filled lymphatic vessel, morphogenesis and maturation, compensation
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-356488ISBN: 978-91-513-0406-9 (print)OAI: oai:DiVA.org:uu-356488DiVA, id: diva2:1239210
Public defence
2018-10-05, Rudbeck Hall, Dag Hammarskjölds v 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-09-10 Created: 2018-08-15 Last updated: 2018-10-02
List of papers
1. cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels
Open this publication in new window or tab >>cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels
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2015 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 10, p. 1708-1721Article in journal (Refereed) Published
Abstract [en]

Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110 alpha PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-251417 (URN)10.1016/j.celrep.2015.02.026 (DOI)000351316700008 ()
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-08-15Bibliographically approved
2. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity
Open this publication in new window or tab >>Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity
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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
Keywords
Lymphatic vasculature, PDGFB, Contraction, Lymphedema, Morphogenesis, Smooth muscle cell
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-337076 (URN)10.1242/dev.147967 (DOI)000412120700018 ()28851707 (PubMedID)
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-646849
Available from: 2018-02-01 Created: 2018-02-01 Last updated: 2018-08-15Bibliographically approved
3. Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels
Open this publication in new window or tab >>Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels
2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 3, article id dev156745Article in journal (Refereed) Published
Abstract [en]

Maintenance of blood vessel integrity is crucial for vascular homeostasis and is mainly controlled at the level of endothelial cell (EC) junctions. Regulation of endothelial integrity has largely been investigated in the mature quiescent vasculature. Less is known about how integrity is maintained during vascular growth and remodeling involving extensive junctional reorganization. Here, we show that embryonic mesenteric blood vascular remodeling is associated with a transient loss of venous integrity and concomitant extravasation of red blood cells (RBCs), followed by their clearance by the developing lymphatic vessels. In wild-type mouse embryos, we observed activated platelets extending filopodia at sites of inter-EC gaps. In contrast, embryos lacking the activatory C-type lectin domain family 1, member b (CLEC1B) showed extravascular platelets and an excessive number of RBCs associated with and engulfed by the first lymphatic EC clusters that subsequently form lumenized blood-filled vessels connecting to the lymphatic system. These results uncover novel functions of platelets in maintaining venous integrity and lymphatic vessels in clearing extravascular RBCs during developmental remodeling of the mesenteric vasculature. They further provide insight into how vascular abnormalities characterized by blood-filled lymphatic vessels arise.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD, 2018
Keywords
Platelet, Lymphvasculogenesis, Endothelial integrity, Blood-filled lymphatic vessel
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-347085 (URN)10.1242/dev.156745 (DOI)000424653300006 ()
Funder
EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Swedish Research Council, 542-2014-3535German Research Foundation (DFG), STR 1538/1-1
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-08-15Bibliographically approved
4. Alternative lymphatic endothelial progenitor cells compensate for the loss of non-venous-derived progenitors to form mesenteric lymphatic vessels
Open this publication in new window or tab >>Alternative lymphatic endothelial progenitor cells compensate for the loss of non-venous-derived progenitors to form mesenteric lymphatic vessels
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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-356486 (URN)
Available from: 2018-07-30 Created: 2018-07-30 Last updated: 2018-08-15

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