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Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.ORCID-id: 0000-0002-3436-3278
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.ORCID-id: 0000-0002-9338-1257
2018 (engelsk)Inngår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, nr 3, artikkel-id dev156745Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
COMPANY OF BIOLOGISTS LTD , 2018. Vol. 145, nr 3, artikkel-id dev156745
Emneord [en]
Platelet, Lymphvasculogenesis, Endothelial integrity, Blood-filled lymphatic vessel
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-347085DOI: 10.1242/dev.156745ISI: 000424653300006OAI: oai:DiVA.org:uu-347085DiVA, id: diva2:1193724
Forskningsfinansiär
EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Swedish Research Council, 542-2014-3535German Research Foundation (DFG), STR 1538/1-1Tilgjengelig fra: 2018-03-27 Laget: 2018-03-27 Sist oppdatert: 2018-08-15bibliografisk kontrollert
Inngår i avhandling
1. Organ-specific mechanisms of vascular development in the mesentery
Åpne denne publikasjonen i ny fane eller vindu >>Organ-specific mechanisms of vascular development in the mesentery
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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).

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 73
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1485
Emneord
Lymphatic vasculature, mesentery, hemogenic endothelium, lymphvasculogenesis, endothelial integrity, platelet, blood-filled lymphatic vessel, morphogenesis and maturation, compensation
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-356488 (URN)978-91-513-0406-9 (ISBN)
Disputas
2018-10-05, Rudbeck Hall, Dag Hammarskjölds v 20, Uppsala, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-09-10 Laget: 2018-08-15 Sist oppdatert: 2018-10-02

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