Genetic Reduction of Vascular Endothelial Growth Factor Receptor 2 Rescues Aberrant Angiogenesis Caused by Epsin Deficiency

Tessneer, Kandice L.; Pasula, Satish; Cai, Xiaofeng; Dong, Yunzhou; McManus, John; Liu, Xiaolei; Yu, Lili; Hahn, Scott; Chang, Baojun; Chen, Yiyuan; Griffin, Courtney T.; Xia, Lijun; Adams, Ralf H.; Chen, Hong

doi:10.1161/atvbaha.113.302586

Cited by 44 publications

(93 citation statements)

References 39 publications

(49 reference statements)

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“…Additionally, a recent study has proposed that reduced VEGF signalling upon depletion of CHC might be simply due to the enhanced degradation of VEGFR2, rather than due to a direct effect of this trafficking route in signalling (Fearnley et al, 2016). In any case, our findings are in line with the predominant and most recent view that CME is not required for VEGF signalling (Bruns et al, 2010;Lampugnani et al, 2006;Lee et al, 2014;Pasula et al, 2012;Tessneer et al, 2014). Thus, all in all, it appears that CME of VEGFR2 is not necessary for signalling to ERK1/2 (Bruns et al, 2010;Lampugnani et al, 2006;Lee et al, 2014;Pasula et al, 2012;Tessneer et al, 2014; and present study) whereas macropinocytosis is absolutely essential ( present study).…”

Section: Discussionsupporting

confidence: 92%

“…Our data suggest that CME is not required for VEGF signalling to ERK1/2 or to Akt, whereas macropinocytosis is crucial. This finding is consistent with previous studies showing that CME is not essential for VEGF-mediated activation of the downstream signalling cascades (Bruns et al, 2010;Lampugnani et al, 2006;Lee et al, 2014;Pasula et al, 2012;Tessneer et al, 2014). However, in contrast to these data, other studies have reported that CME is required for VEGF-mediated downstream signalling (Gourlaouen et al, 2013;Nakayama et al, 2013).…”

Section: Discussionsupporting

confidence: 92%

“…2014). However, intriguingly, several studies have reported that VEGFR2 degradation persists even when the clathrin pathway is blocked (Bhattacharya et al, 2005;Fearnley et al, 2016;Gourlaouen et al, 2013;Pasula et al, 2012;Tessneer et al, 2014), which suggests that VEGFR2 is also internalised through a route that is independent of clathrin. Indeed, the data presented here suggest that, following activation with VEGF, the preferred route of endocytosis of VEGFR2 is macropinocytosis, whereas, unexpectedly, only a minor fraction of VEGFR2 internalises by CME.…”

Section: Discussionmentioning

confidence: 99%

“…However, our understanding on the different routes that are responsible for VEGFR2 internalisation remains limited. Thus, until now, the only known endocytic route for VEGFR2 has been the canonical clathrin-mediated pathway (Bhattacharya et al, 2005;Bruns et al, 2010Bruns et al, , 2012Ewan et al, 2006;Gourlaouen et al, 2013;Lampugnani et al, 2006;Lee et al, 2014;Nakayama et al, 2013;Pasula et al, 2012;Sawamiphak et al, 2010;Tessneer et al, 2014), and its importance in VEGF signalling is debated (Bruns et al, 2010;Gourlaouen et al, 2013;Lampugnani et al, 2006;Lee et al, 2014;Pasula et al, 2012;Tessneer et al, 2014). Intriguingly, VEGF-induced degradation of VEGFR2 persists upon inhibition of clathrin-mediated endocytosis (CME) (Bhattacharya et al, 2005;Fearnley et al, 2016;Gourlaouen et al, 2013;Pasula et al, 2012;Tessneer et al, 2014), thereby suggesting that the receptor might also internalise through clathrin-independent endocytic routes, a possibility that remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

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VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

Basagiannis¹,

Zografou²,

Murphy³

et al. 2016

Development

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Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway for VEGFR2 is the clathrin-mediated pathway. Here, we show that this pathway is the predominant internalisation route for VEGFR2 only in the absence of ligand. Intriguingly, VEGFA induces a new internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route for the receptor in the presence of ligand, whereas the contribution of the clathrin-mediated route becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated through the small GTPase CDC42, takes place through macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays a crucial role in VEGFAinduced signalling, endothelial cell functions in vitro and angiogenesis in vivo, whereas clathrin-mediated endocytosis is not essential for VEGFA signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA-driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

Basagiannis¹,

Zografou²,

Murphy³

et al. 2016

Development

View full text Add to dashboard Cite

show abstract

“…Similarly to other receptor-tyrosine kinases, activation of VEGFR2 by VEGF results in receptor internalization into the endocytic compartments (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). However, unlike the typical activation-dependent internalization of receptor-tyrosine kinases, VEGFR2 undergoes efficient endocytosis even in the absence of VEGF (13,25,26), via the clathrin-mediated route (13).…”

mentioning

confidence: 99%

Constitutive Endocytosis of VEGFR2 Protects the Receptor against Shedding

Basagiannis

Christoforidis

2016

Journal of Biological Chemistry

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VEGFR2 plays a fundamental role in blood vessel formation and in life threatening diseases, such as cancer angiogenesis and cardiovascular disorders. Although inactive growth factor receptors are mainly localized at the plasma membrane, VEGFR2 undergoes constitutive endocytosis (in the absence of ligand) and recycling. Intriguingly, the significance of these futile transport cycles of VEGFR2 remains unclear. Here we found that, unexpectedly, the function of constitutive endocytosis of VEGFR2 is to protect the receptor against plasma membrane cleavage (shedding), thereby preserving the functional state of the receptor until the time of activation by VEGF. Inhibition of constitutive endocytosis of VEGFR2, by interference with the function of clathrin, dynamin, or Rab5, increases dramatically the cleavage/shedding of VEGFR2. Shedding of VEGFR2 produces an N-terminal soluble fragment (100 kDa, s100), which is released in the extracellular space, and a residual C-terminal part (130 kDa, p130) that remains integrated at the plasma membrane. The released soluble fragment (s100) co-immunoprecipitates with VEGF, in line with the topology of the VEGF-binding domain at the N terminus of VEGFR2. Increased shedding of VEGFR2 (via inhibition of constitutive endocytosis) results in reduced response to VEGF, consistently with the loss of the VEGF-binding domain from the membrane remnant of VEGFR2. These data suggest that constitutive internalization of VEGFR2 protects the receptor against shedding and provides evidence for an unprecedented mechanism via which endocytosis can regulate the fate and activity of growth factor receptors.Growth factor receptors are synthesized and processed in the ER/Golgi biosynthetic network. Subsequently, they are delivered to the plasma membrane to become available for binding to their extracellular cognate ligands. In principle, in the absence of ligand, quiescent receptors are preferentially localized at the plasma membrane, whereas only a small percentage of the surface molecules are constitutively internalized (1-3). On the other hand, ligand binding and subsequent receptor activation increases dramatically the efficiency of receptor internalization (3, 4). Internalized receptors explore the different endocytic itineraries and the diverse endocytic compartments to finetune the intensity, nature, and duration of the signaling events (2, 4, 5). Subsequently, growth factor receptors are either recycled back to plasma membrane, for another round of activation, or they are sorted to lysosomes or the proteasome for degradation, leading to irreversible termination of the receptor function (6). In fact, in general, the degradative role of endocytosis is considered to be one of the major housekeeping functions of the cell that eventually down-regulates the levels of the internalized, extracellular or plasma membrane, molecules (7-9).VEGFR2 is a receptor-tyrosine kinase that plays a critical role in blood vessel formation and pathological angiogenesis (10,11). Similarly to other receptor-tyrosine kinas...

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Epsin Mimetic UPI Peptide Delivery Strategies to Improve Endothelization of Vascular Grafts

Changizi

Sameti

Bazemore

et al. 2023

Macromolecular Bioscience

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Endothelialization of engineered vascular grafts for replacement of small‐diameter coronary arteries remains a critical challenge. The ability for an acellular vascular graft to promote endothelial cell (EC) recruitment in the body would be very beneficial. This study investigated epsins as a target since they are involved in internalization of vascular endothelial growth factor receptor 2. Specifically, epsin‐mimetic UPI peptides are delivered locally from vascular grafts to block epsin activity and promote endothelialization. The peptide delivery from fibrin coatings allowed for controlled loading and provided a significant improvement in EC attachment, migration, and growth in vitro. The peptides have even more important impacts after grafting into rat abdominal aortae. The peptides prevented graft thrombosis and failure that is observed with a fibrin coating alone. They also modulated the in vivo remodeling. The grafts are able to remodel without the formation of a thick fibrous capsule on the adventitia with the 100 µg mL−1 peptide‐loaded condition, and this condition enabled the formation of a functional EC monolayer in the graft lumen after only 1 week. Overall, this study demonstrated that the local delivery of UPI peptides is a promising strategy to improve the performance of vascular grafts.

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Genetic Reduction of Vascular Endothelial Growth Factor Receptor 2 Rescues Aberrant Angiogenesis Caused by Epsin Deficiency

Cited by 44 publications

References 39 publications

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

Constitutive Endocytosis of VEGFR2 Protects the Receptor against Shedding

Epsin Mimetic UPI Peptide Delivery Strategies to Improve Endothelization of Vascular Grafts

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