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Claesson-Welsh, LenaORCID iD iconorcid.org/0000-0003-4275-2000
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Publications (10 of 147) Show all publications
Sáinz-Jaspeado, M., Ring, S., Proulx, S. T., Richards, M., Martinsson, P., Li, X., . . . Jin, Y. (2024). VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis. Life Science Alliance, 7(3), Article ID E202302168.
Open this publication in new window or tab >>VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis
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2024 (English)In: Life Science Alliance, E-ISSN 2575-1077, Vol. 7, no 3, article id E202302168Article in journal (Refereed) Published
Abstract [en]

The endothelial junction component vascular endothelial (VE)–cadherin governs junctional dynamics in the blood and lymphatic vasculature. Here, we explored how lymphatic junction stability is modulated by elevated VEGFA signaling to facilitate metastasis to sentinel lymph nodes. Zippering of VE-cadherin junctions was established in dermal initial lymphatic vessels after VEGFA injection and in tumor-proximal lymphatics in mice. Shape analysis of pan-cellular VE-cadherin fragments revealed that junctional zippering was accompanied by accumulation of small round-shaped VE-cadherin fragments in the lymphatic endothelium. In mice expressing a mutant VEGFR2 lacking the Y949 phosphosite (Vegfr2Y949F/Y949F) required for activation of Src family kinases, zippering of lymphatic junctions persisted, whereas accumulation of small VE-cadherin fragments was suppressed. Moreover, tumor cell entry into initial lymphatic vessels and subsequent metastatic spread to lymph nodes was reduced in mutant mice compared with WT, after challenge with B16F10 melanoma or EO771 breast cancer. We conclude that VEGFA mediates zippering of VE-cadherin junctions in initial lymphatics. Zippering is accompanied by increased VE-cadherin fragmentation through VEGFA-induced Src kinase activation, correlating with tumor dissemination to sentinel lymph nodes.

Place, publisher, year, edition, pages
Life Science Alliance, 2024
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-522271 (URN)10.26508/lsa.202302168 (DOI)001134104300002 ()38148112 (PubMedID)
Funder
Swedish Research Council, 2016-02492Swedish Cancer Society, 20 0970 PjFSwedish Research Council, 2022-00896Stiftelsen G A Johanssons MinnesfondP.O. Zetterling FoundationSwedish Cancer Society, 2017/759Kjell and Marta Beijer FoundationSwedish Cancer Society, 22 2029 Pj 01 HKnut and Alice Wallenberg Foundation, KAW 2020.0057The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), CH2018-7817
Available from: 2024-02-05 Created: 2024-02-05 Last updated: 2024-02-05Bibliographically approved
Lugano, R., Vemuri, K., Barbera, S., Orlandini, M., Dejana, E., Claesson-Welsh, L. & Dimberg, A. (2023). CD93 maintains endothelial barrier function by limiting the phosphorylation and turnover of VE-cadherin. The FASEB Journal, 37(4), Article ID e22894.
Open this publication in new window or tab >>CD93 maintains endothelial barrier function by limiting the phosphorylation and turnover of VE-cadherin
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2023 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 37, no 4, article id e22894Article in journal (Refereed) Published
Abstract [en]

Regulation of vascular permeability to plasma is essential for tissue and organ homeostasis and is mediated by endothelial cell-to-cell junctions that tightly regulate the trafficking of molecules between blood and tissue. The single-pass transmembrane glycoprotein CD93 is upregulated in endothelial cells during angiogenesis and controls cytoskeletal dynamics. However, its role in maintaining homeostasis by regulating endothelial barrier function has not been elucidated yet. Here, we demonstrate that CD93 interacts with vascular endothelial (VE)-cadherin and limits its phosphorylation and turnover. CD93 deficiency in vitro and in vivo induces phosphorylation of VE-cadherin under basal conditions, displacing it from endothelial cell–cell contacts. Consistent with this, endothelial junctions are defective in CD93−/− mice, and the blood–brain barrier permeability is enhanced. Mechanistically, CD93 regulates VE-cadherin phosphorylation and turnover at endothelial junctions through the Rho/Rho kinase-dependent pathway. In conclusion, our results identify CD93 as a key regulator of VE-cadherin stability at endothelial junctions, opening up possibilities for therapeutic strategies directed to control vascular permeability.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
blood-brain barrier, CD93, endothelial junctions, RhoGTPases, vascular permeability, VE-cadherin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-500304 (URN)10.1096/fj.202201623RR (DOI)000955669800001 ()36961390 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, 20 1008 PjFSwedish Cancer Society, 20 1010 UsFKnut and Alice Wallenberg Foundation, 2019.0088Swedish Research Council, 2020-02563Swedish Childhood Cancer Foundation, PR2018-0148Swedish Childhood Cancer Foundation, PR2021-0122The Swedish Brain Foundation, FO2022-0366
Available from: 2023-04-18 Created: 2023-04-18 Last updated: 2023-05-23Bibliographically approved
Zarkada, G., Chen, X., Zhou, X., Lange, M., Zeng, L., Lv, W., . . . Zhang, F. (2023). Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption. Circulation Research, 133(4), 333-349
Open this publication in new window or tab >>Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption
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2023 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 133, no 4, p. 333-349Article in journal (Refereed) Published
Abstract [en]

Background: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood.

Methods: We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries.

Results: By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction.

Conclusions: Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2023
Keywords
chylomicrons, endothelial cells, lipid, permeability, vascular endothelial growth factor A
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-510353 (URN)10.1161/CIRCRESAHA.123.322607 (DOI)001041566200004 ()37462027 (PubMedID)
Available from: 2023-08-28 Created: 2023-08-28 Last updated: 2023-08-28Bibliographically approved
Sjöberg, E., Melssen, M., Richards, M., Ding, Y., Chanoca, C., Chen, D., . . . Claesson-Welsh, L. (2023). Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src. Journal of Clinical Investigation, 133(20), Article ID e161366.
Open this publication in new window or tab >>Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src
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2023 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 133, no 20, article id e161366Article in journal (Refereed) Published
Abstract [en]

Endothelial phospholipase C gamma (PLC gamma) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLC gamma was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLC gamma expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLC gamma was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLC gamma (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo-and immunotherapy. Mechanistically, pY1173/PLC gamma signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLC gamma/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLC gamma and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLC gamma pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.

Place, publisher, year, edition, pages
American Society For Clinical Investigation, 2023
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-520381 (URN)10.1172/JCI161366 (DOI)001127596500002 ()37651195 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation, 2020-01349Swedish Cancer Society, 17 CVD 03
Available from: 2024-01-12 Created: 2024-01-12 Last updated: 2024-01-12Bibliographically approved
Vestweber, D., Claesson-Welsh, L., McDonald, D. M., Williams, T., Schwartz, M. A., Scallan, J., . . . Simons, M. (2023). Report from the 2023 workshop on endothelial permeability, edema and inflammation. Nature Cardiovascular Research, 2(12), 1120-1124
Open this publication in new window or tab >>Report from the 2023 workshop on endothelial permeability, edema and inflammation
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2023 (English)In: Nature Cardiovascular Research, E-ISSN 2731-0590, Vol. 2, no 12, p. 1120-1124Article in journal, Editorial material (Other academic) Published
Abstract [en]

A key consequence of increased and sustained vascular permeability in several inflammatory and cardiovascular disorders is the development of interstitial protein-rich proinflammatory edema. This response remains poorly understood mechanistically and its potential adverse effect on local and systemic diseases is often underestimated. To discuss current findings and identify crucial unresolved questions, a workshop was held in Berlin from 12-15 April 2023. Key topics that were discussed included regulation of endothelial cell junctions, neutrophil-dependent vascular leakage, resolution of edema, exemplar diseases, and anti-edema therapies. This report is a summary of the meeting.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cardiac and Cardiovascular Systems Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-523464 (URN)10.1038/s44161-023-00385-w (DOI)001124837200018 ()
Available from: 2024-02-21 Created: 2024-02-21 Last updated: 2024-02-21Bibliographically approved
Richards, M., Nwadozi, E., Pal, S., Martinsson, P., Kaakinen, M., Gloger, M., . . . Claesson-Welsh, L. (2022). Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner. eLIFE, 11, Article ID e78517.
Open this publication in new window or tab >>Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner
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2022 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e78517Article in journal (Refereed) Published
Abstract [en]

Dysfunctional and leaky blood vessels resulting from disruption of the endothelial cell (EC) barrier accompanies numerous diseases. The EC barrier is established through endothelial cell tight and adherens junctions. However, the expression pattern and precise contribution of different junctional proteins to the EC barrier is poorly understood. Here, we focus on organs with continuous endothelium to identify structural and functional in vivo characteristics of the EC barrier. Assembly of multiple single-cell RNAseq datasets into a single integrated database revealed the variability and commonalities of EC barrier patterning. Across tissues, Claudin5 exhibited diminishing expression along the arteriovenous axis, correlating with EC barrier integrity. Functional analysis identified tissue-specific differences in leakage properties and response to the leakage agonist histamine. Loss of Claudin5 enhanced histamine-induced leakage in an organotypic and vessel type-specific manner in an inducible, EC-specific, knock-out mouse. Mechanistically, Claudin5 loss left junction ultrastructure unaffected but altered its composition, with concomitant loss of zonula occludens-1 and upregulation of VE-Cadherin expression. These findings uncover the organ-specific organisation of the EC barrier and distinct importance of Claudin5 in different vascular beds, providing insights to modify EC barrier stability in a targeted, organ-specific manner.

Place, publisher, year, edition, pages
eLife Sciences Publications LtdeLIFE SCIENCES PUBL LTD, 2022
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-487895 (URN)10.7554/eLife.78517 (DOI)000868312900001 ()35861713 (PubMedID)
Funder
Swedish Research Council, 2020-01349Knut and Alice Wallenberg Foundation, 2020.0057Knut and Alice Wallenberg Foundation, 2019.0276Knut and Alice Wallenberg Foundation, 2017.0144Swedish Cancer Society, 19 0118Swedish Cancer Society, 20 1086Ragnar Söderbergs stiftelse, M13/17Åke Wiberg Foundation, M21-0109Swedish Society for Medical Research (SSMF), 201912
Available from: 2022-11-11 Created: 2022-11-11 Last updated: 2024-01-15Bibliographically approved
Boye, K., Geraldo, L. H., Furtado, J., Pibouin-Fragner, L., Poulet, M., Kim, D., . . . Eichmann, A. (2022). Endothelial Unc5B controls blood-brain barrier integrity. Nature Communications, 13(1), Article ID 1169.
Open this publication in new window or tab >>Endothelial Unc5B controls blood-brain barrier integrity
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 1169Article in journal (Refereed) Published
Abstract [en]

The authors show that Netrin-1-Unc5B signaling controls blood-brain barrier integrity by maintaining Wnt/b-catenin signaling and that delivery of antibodies blocking Netrin-1 binding to Unc5B causes transient and size-selective BBB breakdown. Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/beta-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression. Loss of Unc5B decreases BBB Wnt/beta-catenin signaling, and beta-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt co-receptor LRP6, induces its phosphorylation and activates Wnt/beta-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-471679 (URN)10.1038/s41467-022-28785-9 (DOI)000764895600004 ()35246514 (PubMedID)
Funder
EU, European Research Council, 834161
Available from: 2022-04-04 Created: 2022-04-04 Last updated: 2024-01-15Bibliographically approved
Maeso-Alonso, L., Alonso-Olivares, H., Martinez-Garcia, N., Lopez-Ferreras, L., Villoch-Fernandez, J., Puente-Santamaria, L., . . . Marin, M. C. (2022). p73 is required for vessel integrity controlling endothelial junctional dynamics through Angiomotin. Cellular and Molecular Life Sciences (CMLS), 79(10), Article ID 535.
Open this publication in new window or tab >>p73 is required for vessel integrity controlling endothelial junctional dynamics through Angiomotin
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2022 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 79, no 10, article id 535Article in journal (Refereed) Published
Abstract [en]

Preservation of blood vessel integrity, which is critical for normal physiology and organ function, is controlled at multiple levels, including endothelial junctions. However, the mechanism that controls the adequate assembly of endothelial cell junctions is not fully defined. Here, we uncover TAp73 transcription factor as a vascular architect that orchestrates transcriptional programs involved in cell junction establishment and developmental blood vessel morphogenesis and identify Angiomotin (AMOT) as a TAp73 direct transcriptional target. Knockdown of p73 in endothelial cells not only results in decreased Angiomotin expression and localization at intercellular junctions, but also affects its downstream function regarding Yes-associated protein (YAP) cytoplasmic sequestration upon cell-cell contact. Analysis of adherens junctional morphology after p73-knockdown in human endothelial cells revealed striking alterations, particularly a sharp increase in serrated junctions and actin bundles appearing as stress fibers, both features associated with enhanced barrier permeability. In turn, stabilization of Angiomotin levels rescued those junctional defects, confirming that TAp73 controls endothelial junction dynamics, at least in part, through the regulation of Angiomotin. The observed defects in monolayer integrity were linked to hyperpermeability and reduced transendothelial electric resistance. Moreover, p73-knockout retinas showed a defective sprout morphology coupled with hemorrhages, highlighting the physiological relevance of p73 regulation in the maintenance of vessel integrity in vivo. We propose a new model in which TAp73 acts as a vascular architect integrating transcriptional programs that will impinge with Angiomotin/YAP signaling to maintain junctional dynamics and integrity, while balancing endothelial cell rearrangements in angiogenic vessels.

Place, publisher, year, edition, pages
Springer Nature, 2022
Keywords
p53 family, Cell junctions, Endothelial barrier integrity, Vascular morphogenesis, Actin cytoskeleton, VE-cadherin and angiogenesis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-486667 (URN)10.1007/s00018-022-04560-3 (DOI)000862402800001 ()36180740 (PubMedID)
Available from: 2022-10-17 Created: 2022-10-17 Last updated: 2022-10-17Bibliographically approved
Persson Skare, T., Kaito, H., Durall, C., Aastrup, T. & Claesson-Welsh, L. (2022). Quartz Crystal Microbalance Measurement of Histidine-Rich Glycoprotein and Stanniocalcin-2 Binding to Each Other and to Inflammatory Cells. Cells, 11(17), Article ID 2684.
Open this publication in new window or tab >>Quartz Crystal Microbalance Measurement of Histidine-Rich Glycoprotein and Stanniocalcin-2 Binding to Each Other and to Inflammatory Cells
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2022 (English)In: Cells, E-ISSN 2073-4409, Vol. 11, no 17, article id 2684Article in journal (Refereed) Published
Abstract [en]

The plasma protein histidine-rich glycoprotein (HRG) is implicated in the polarization of macrophages to an M1 antitumoral phenotype. The broadly expressed secreted protein stanniocalcin 2 (STC2), also implicated in tumor inflammation, is an HRG interaction partner. With the aim to biochemically characterize the HRG and STC2 complex, binding of recombinant HRG and STC2 preparations to each other and to cells was explored using the quartz crystal microbalance (QCM) methodology. The functionality of recombinant proteins was tested in a phagocytosis assay, where HRG increased phagocytosis by monocytic U937 cells while STC2 suppressed HRG-induced phagocytosis. The binding of HRG to STC2, measured using QCM, showed an affinity between the proteins in the nanomolar range, and both HRG and STC2 bound individually and in combination to vitamin D3-treated, differentiated U937 monocytes. HRG, but not STC2, also bound to formaldehyde-fixed U937 cells irrespective of their differentiation stage in part through the interaction with heparan sulfate. These data show that HRG and STC2 bind to each other as well as to U937 monocytes with high affinity, supporting the relevance of these interactions in monocyte/macrophage polarity.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
histidine-rich glycoprotein, stanniocalcin-2, protein complex, inflammatory cells, quartz crystal microbalance
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-484792 (URN)10.3390/cells11172684 (DOI)000851082100001 ()36078092 (PubMedID)
Funder
Swedish Cancer Society, 19 0119 Pj 01Swedish Research Council, 2020-01349Knut and Alice Wallenberg Foundation, KAW 2020.0057
Available from: 2022-09-19 Created: 2022-09-19 Last updated: 2022-09-19Bibliographically approved
Zhou, W., Liu, K., Zeng, L., He, J., Gao, X., Gu, X., . . . Chen, Y. (2022). Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension. Circulation, 146(24), 1855-1881
Open this publication in new window or tab >>Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension
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2022 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 146, no 24, p. 1855-1881Article in journal (Refereed) Published
Abstract [en]

Background:Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. Methods:VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2(Y949F)) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. Results:We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2(Y949F) point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. Conclusions:Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2022
Keywords
hypoxic pulmonary hypertension, macrophage, single-cell RNA sequencing, smooth muscle, Src family kinase, vascular permeability, VEGF-A, VEGFR2 Y949
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-494721 (URN)10.1161/CIRCULATIONAHA.122.061900 (DOI)000898657500009 ()36384284 (PubMedID)
Available from: 2023-02-10 Created: 2023-02-10 Last updated: 2023-02-10Bibliographically approved
Projects
Time-lapse microscopy to follow cell locomotion in health and disease [2008-05868_VR]; Uppsala UniversityInflamamtion and angiogenesis: new treatment strategy [2009-00189_VINNOVA]; Uppsala UniversityVascular endothelial growth factor biology in health and disease [2010-02521_VR]; Uppsala UniversityVascular permeability in health and disease; deciphering the barrier function [2015-02375_VR]; Uppsala UniversityRegulatory mechanisms of vascular leakage, towards new treatments of eye diseases [2020-01349_VR]; Uppsala UniversityVascular leakage and its role in disease [2022-00896_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4275-2000

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