Evolutionary Differences in the Vegf/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis

Vogrin, Adam; Bower, Neil I.; Gunzburg, Menachem J.; Roufail, Sally; Okuda, Kazuhide S.; Paterson, Scott; Headey, Stephen J.; Stacker, Steven A.; Hogan, Benjamin M.; Achen, Marc G.

doi:10.1016/j.celrep.2019.07.055

Cited by 28 publications

(29 citation statements)

References 61 publications

(120 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The homeobox transcription factor Prox1 plays pivotal roles in the development of embryonic lymphatics and in the maintenance of the adult lymphatic system by regulating various LEC related factors, such as VEGFR-3 ( Yang and Oliver, 2014 ). Kdr (a VEGFR-2 homolog) is indispensable for craniofacial lymphangiogenesis in zebrafish and is involved in the proliferation and migration of LECs ( Vogrin et al, 2019 ). c-Jun participates in the proliferation of LECs ( Wissmann and Detmar, 2006 ), while Ets1, an important transcription factor of the Ets family, is required for Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced expression of VEGFR-3 and lymphangiogenesis ( Gutierrez et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…To validate the findings obtained from the microarray (Table 1), we first analyzed the mRNA levels of Kdr, c-Jun (cluster 13), Stc1 (cluster 8), Sparc (cluster 7), and Ets1 (cluster 0), which have been reported to be associated with LECs migration and proliferation or lymphangiogenesis (Wissmann and Detmar, 2006;Gutierrez et al, 2013;Vogrin et al, 2019). The qPCR results revealed that Ang II treatment upregulated the mRNA levels of Kdr, c-Jun and Stc1 but reduced the mRNA levels of Sparc and Ets1 in LECs in a time-dependent manner compared with control ( Figure 7A).…”

Section: Validation Of Gene Expression In Ang Ii-treated Lecs By Qpcrmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

et al. 2020

View full text Add to dashboard Cite

Background/Aim: The proliferation and migration of lymphatic endothelial cells (LECs) is essential for lymphatic vessel growth (also known as lymphangiogenesis), which plays a crucial role in regulating the tissue fluid balance and immune cell trafficking under physiological and pathological conditions. Several growth factors, such as VEGF-C, can stimulate lymphangiogenesis. However, the effects of angiotensin II (Ang II) on the proliferation and migration of mouse LECs and the underlying potential mechanisms remain unknown. Methods: Wild-type mice were infused with Ang II (1,000 ng/kg/min) for 1-2 weeks. Murine LECs were stimulated with Ang II (500 nM) or saline for 12-48 h. Cell proliferation was determined with 5-bromo-2-deoxyuridine (BrdU) incorporation assays, while cell migration was assessed by scratch wound healing and transwell chamber assays. The gene expression profiles were obtained by time series microarray and real-time PCR analyses. Results: Ang II treatment significantly induced lymphangiogenesis in the hearts of mice and the proliferation and migration of cultured LECs in a time-dependent manner. This effect was completely blocked by losartan, an angiotensin II type 1 receptor (AT1R) antagonist. The microarray results identified 1,385 differentially expressed genes (DEGs) at one or more time points in the Ang II-treated cells compared with the control salinetreated cells. These DEGs were primarily involved in biological processes and pathways, including sensory perception of smell, the G protein coupled receptor signaling pathway, cell adhesion, olfactory transduction, Jak-STAT, alcoholism, RIG-I-like receptor and ECM-receptor interaction. Furthermore, these DEGs were classified into 16 clusters, 7 of which (Nos. 13, 2, 8, 15, 7, 3, and 12, containing 586 genes) were statistically significant. Importantly, the Ang II-induced alterations the expression of lymphangiogenesis-related genes were reversed by losartan.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Validation Of Gene Expression In Ang Ii-treated Lecs By Qpcrmentioning

confidence: 99%

Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The formation of the craniofacial lymphatic vasculature occurs in a very different manner to lymphatics in other tissues and provides compelling evidence for heterogeneity in developmental and cellular processes ( Okuda et al, 2012 ; Astin et al, 2014 ; Shin et al, 2016b , 2019 ; Eng et al, 2019 ; Vogrin et al, 2019 ). For example, Eng and colleagues lineage traced cells that contribute to facial lymphatics using the photoconvertible Kaede protein.…”

Section: Heterogeneity In Cellular Mechanisms In Zebrafish Vascular Dmentioning

confidence: 99%

Endothelial Cell Dynamics in Vascular Development: Insights From Live-Imaging in Zebrafish

Okuda

Hogan

2020

Front. Physiol.

Self Cite

View full text Add to dashboard Cite

The formation of the vertebrate vasculature involves the acquisition of endothelial cell identities, sprouting, migration, remodeling and maturation of functional vessel networks. To understand the cellular and molecular processes that drive vascular development, live-imaging of dynamic cellular events in the zebrafish embryo have proven highly informative. This review focusses on recent advances, new tools and new insights from imaging studies in vascular cell biology using zebrafish as a model system.

show abstract

“…However, even murine VEGF-D reportedly differs from human VEGF-D in its inability to interact with mouse VEGFR-2 [68]. Exactly the opposite seems to be the case in zebrafish, where the VEGF-D-VEGFR-3 interaction was reported to be absent [69], implying that lymphangiogenesis might happen in zebrafish independently of VEGFR-3. While direct demonstrations of the substrate specificities of the zebrafish Adamts proteases are still missing, it appears clear that zebrafish data are not easily extrapolated to mammals.…”

Section: Species-specific Differencesmentioning

confidence: 98%

The Proteolytic Activation of Vascular Endothelial Growth Factors

Künnapuu¹,

Bokharaie²,

Jeltsch³

2021

Preprint

View full text Add to dashboard Cite

Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymphangiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. The activating cleavage of VEGF-C is mediated by at least five different proteases: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the "mature" growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by different proteases. During embryonic development, ADAMTS3 activates VEGF-C. In contrast, thrombin and plasmin likely activate VEGF-C/-D during tissue injury-induced lymphangiogenesis, and PSA and cathepsin D perhaps during tumor-associated pathological lymphangiogenesis. Additionally, cathepsin D from saliva might activate latent VEGF-C/-D upon wound licking, thereby accelerating healing. Similar to tyrosine kinase receptors and VEGFs themselves, these activating proteases could be targeted to modulate angiogenesis and lymphangiogenesis in relevant diseases.

show abstract

Evolutionary Differences in the Vegf/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis

Cited by 28 publications

References 61 publications

Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

Endothelial Cell Dynamics in Vascular Development: Insights From Live-Imaging in Zebrafish

The Proteolytic Activation of Vascular Endothelial Growth Factors

Contact Info

Product

Resources

About