Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

AbstractFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

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Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

10.1101/2020.06.17.157131 ◽

2020 ◽

Author(s):

Delphine M. Lees ◽

Louise E. Reynolds ◽

Ana Rita Pedrosa ◽

Marina Roy-Luzarraga ◽

Kairbaan M. Hodivala-Dilke

Keyword(s):

Blood Vessel ◽

Tumour Growth ◽

Vascular Endothelial Cell ◽

Growth Control ◽

Vessel Density ◽

Blood Vessel Density ◽

Tumour Vessel ◽

Vessel Regression ◽

Tumour Blood

AbstractFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre+;FAKWT/WT, PdgfrβCre+;FAKY397F/Y397F and PdgfrβCre+;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre+;FAKY861F/Y861F but not PdgfrβCre+;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of a pericyte derived ‘pericrine’ signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

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Immunohistochemistry Evaluation of the Effect in Vivo of Tumor Necrosis Factor (TNF)-α on Blood Vessel Density in Murine Fibrosarcoma

Sarcoma ◽

10.1080/13577140310001607275 ◽

2003 ◽

Vol 7 (2) ◽

pp. 57-61 ◽

Cited By ~ 3

Author(s):

Avi Eisenthal ◽

Ignat Schwartz ◽

Josephine Issakov ◽

Yossef Klausner ◽

Faina Misonzhnik ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Blood Vessel ◽

Tumor Necrosis ◽

Vessel Density ◽

Blood Vessel Density ◽

Tnf Α ◽

Murine Fibrosarcoma ◽

Necrosis Factor

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In Vivo Tumor Vascular Imaging with Light Emitting Diode-Based Photoacoustic Imaging System

Sensors ◽

10.3390/s20164503 ◽

2020 ◽

Vol 20 (16) ◽

pp. 4503 ◽

Cited By ~ 1

Author(s):

Marvin Xavierselvan ◽

Mithun Kuniyil Ajith Singh ◽

Srivalleesha Mallidi

Keyword(s):

Cancer Research ◽

Blood Vessel ◽

Imaging System ◽

Light Emitting Diode ◽

Tumor Vasculature ◽

Vessel Density ◽

Excitation Wavelength ◽

Light Emitting ◽

Blood Vessel Density

Photoacoustic (PA) imaging has shown tremendous promise for imaging tumor vasculature and its function at deeper penetration depths without the use of exogenous contrast agents. Traditional PA imaging systems employ expensive and bulky class IV lasers with low pulse repetition rate, due to which its availability for preclinical cancer research is hampered. In this study, we evaluated the capability of a Light-Emitting Diode (LED)-based PA and ultrasound (US) imaging system for monitoring heterogeneous microvasculature in tumors (up to 10 mm in depth) and quantitatively compared the PA images with gold standard histology images. We used a combination of a 7 MHz linear array US transducer and 850 nm excitation wavelength LED arrays to image blood vessels in a subcutaneous tumor model. After imaging, the tumors were sectioned and stained for endothelial cells to correlate with PA images across similar cross-sections. Analysis of 30 regions of interest in tumors from different mice showed a statistically significant R-value of 0.84 where the areas with high blood vessel density had high PA response while low blood vessel density regions had low PA response. Our results confirm that LED-based PA and US imaging can provide 2D and 3D images of tumor vasculature and the potential it has as a valuable tool for preclinical cancer research.

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Increased Skin Inflammation and Blood Vessel Density in Human and Experimental Diabetes

The International Journal of Lower Extremity Wounds ◽

10.1177/1534734612474303 ◽

2013 ◽

Vol 12 (1) ◽

pp. 4-11 ◽

Cited By ~ 36

Author(s):

Ana Tellechea ◽

Antonios Kafanas ◽

Ermelindo C. Leal ◽

Francesco Tecilazich ◽

Sarada Kuchibhotla ◽

...

Keyword(s):

Blood Vessel ◽

Blood Vessels ◽

Experimental Diabetes ◽

Human Subjects ◽

Inflammatory Cells ◽

Skin Inflammation ◽

Vessel Density ◽

Impaired Wound Healing ◽

Blood Vessel Density ◽

Skin Blood Vessels

Systemic inflammation is associated with impaired wound healing in diabetes mellitus (DM) patients. Using immunohistochemistry techniques, the authors investigated changes in skin inflammation and skin blood vessels in human and experimental diabetes. Comparing to the non-DM human subjects, the total number of inflammatory cells per biopsy and the number of inflammatory cells around blood vessels, a strong indication of inflammation, were higher in DM subjects irrespective of their risk for developing diabetic foot ulcer. Inflammatory cell infiltration was robustly increased in all DM animal models compared with their non-DM controls. The number and density of blood vessels and CD31 positive proliferating endothelial cells around preexisting skin vessels was also higher in the DM patients. However, there were no differences in the skin blood flow between the non-DM and DM subjects. The number of skin blood vessels was also increased in the DM animals; however, these differences were less obvious than the ones observed for inflammatory cells. We conclude that skin inflammation and skin blood vessel density is increased in diabetic human subjects and in rodent and rabbit models of diabetes.

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Prognostic value of blood vessel density in ischaemic stroke

The Lancet ◽

10.1016/0140-6736(93)91734-4 ◽

1993 ◽

Vol 342 (8873) ◽

pp. 742 ◽

Cited By ~ 53

Author(s):

J. Krupinski ◽

J. Kaluza ◽

P. Kumar ◽

M. Wang ◽

S. Kumar

Keyword(s):

Blood Vessel ◽

Ischaemic Stroke ◽

Prognostic Value ◽

Vessel Density ◽

Blood Vessel Density

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Abstract 186: Hdac7-derived 7aa Peptide May Function as a Phosphorylation Carrier

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.186 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Junyao Yang ◽

Wen Wang ◽

Qian Wang ◽

Lingfang Zeng

Keyword(s):

Endothelial Cell ◽

Vascular Endothelial Cell ◽

Blood Perfusion ◽

Open Reading Frames ◽

In Vivo Studies ◽

Buffer System ◽

Vascular Progenitor Cells ◽

Upstream Kinase

Background: Histone deacetylase 7 (HDAC7) belongs to class II HDAC family, playing a pivotal role in the maintenance of endothelium integrity. There are 8 splicing variants in mouse HDAC7 mRNAs. Within the 5’ terminal non-coding area of some variants, there exist some short open reading frames (sORFs). Whether these sORFs can be translated and their potential roles in cellular physiology remain unclear. Method and results: Our previous studies suggested that one mouse HDAC7 produced a 7aa peptide from the non-coding area. In this study, we demonstrated that one sORF encoding a 7 amino acids (aa)-peptide could be translated in response to vascular endothelial cell growth factor (VEGF) in vascular progenitor cells (VPCs). The 7aa-peptide (7A) could be phosphorylated at serine residue via MEKK1. Importantly, the phosphorylated 7aa-peptide (7Ap) could transfer the phosphorylation group to the Thr residue of the 14-3-3γ protein in a cell free in-gel buffer system. The in vitro functional analyses revealed that 7A enhanced VEGF-induced VPC migration and differentiation toward endothelial cell (EC) lineage, in which MEKK1 and 14-3-3γ served as upstream kinase and downstream effector respectively. Knockdown of either MEKK1 or 14-3-3γ attenuated VEGF-induced VPC migration and differentiation. Exogenous 7Ap could rescue VEGF effect in MEKK1 but not in 14-3-3γ knockdown cells. The in vivo studies showed that 7A especially 7Ap induced capillary vessel formation within matrigel plug assays, increased re-endothelialization and suppressed neointima formation in the femoral artery injury model, and promoted the foot blood perfusion recovery in the hindlimb ischemia model. Conclusion: These results indicate that the sORFs within the non-coding area can be translated under some circumstances and that the 7aa-peptide may play an important role in cellular processes like migration and differentiation via acting as a phosphorylation carrier. Significance: As a phosphorylation carrier, 7aa possesses therapeutic potentials in tackling angiogenesis related diseases.

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