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Accelerated coronary angiogenesis by vegfr1-knockout endocardial cells.

Zhang Z, Zhou B - PLoS ONE (2013)

Bottom Line: We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1- hearts.We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells.These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Biotherapy, West China Medical School of Sichuan University, Chengdu, Sichuan, China.

ABSTRACT
During mouse heart development, ventricular endocardial cells give rise to the coronary arteries by angiogenesis. Myocardially-derived vascular endothelial growth factor-a (Vegfa) regulates embryonic coronary angiogenesis through vascular endothelial growth factor-receptor 2 (Vegfr2) expressed in the endocardium. In this study, we investigated the role of endocardially-produced soluble Vegfr1 (sVegfr1) in the coronary angiogenesis. We deleted sVegfr1 in the endocardium of the developing mouse heart and found that this deletion resulted in a precocious formation of coronary plexuses. Using an ex vivo coronary angiogenesis assay, we showed that the Vegfr1- ventricular endocardial cells underwent excessive angiogenesis and generated extensive endothelial tubular networks. We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1- hearts. We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells. These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.

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Working model shows the Vegf-Notch signaling in the ventricular endocardium that regulates coronary angiogenesis by the ventricular endocardial cells.A, Schematics showing that a balanced Vegf signaling in the endocardium (Control) is essential for the coronary angiogenesis by the ventricular endocardial cells. When the Vegf signaling in the endocardium is disrupted by deleting the proangiogenic Vegfr2 (R2 CKO) [27] or the anti-angiogenic Vegfr1 (R1 CKO; this study), the coronary angiogenesis is blocked or accelerated, respectively. B, Diagrams depicting a mode of controlled Vegf-Notch signaling that is necessary for normal coronary angiogenesis. Enhanced Vegf2 signaling in the endocardial cells by removal of the inhibitory sVegfr1 results in the increased Dll4 expression and accelerated augmented coronary angiogenesis whereas blocking Notch signaling prohibits the process (not shown in the diagrams), suggesting that balanced Vegf and Notch signals collaborate in the endocardial cells to control the coronary angiogenesis.
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pone-0070570-g008: Working model shows the Vegf-Notch signaling in the ventricular endocardium that regulates coronary angiogenesis by the ventricular endocardial cells.A, Schematics showing that a balanced Vegf signaling in the endocardium (Control) is essential for the coronary angiogenesis by the ventricular endocardial cells. When the Vegf signaling in the endocardium is disrupted by deleting the proangiogenic Vegfr2 (R2 CKO) [27] or the anti-angiogenic Vegfr1 (R1 CKO; this study), the coronary angiogenesis is blocked or accelerated, respectively. B, Diagrams depicting a mode of controlled Vegf-Notch signaling that is necessary for normal coronary angiogenesis. Enhanced Vegf2 signaling in the endocardial cells by removal of the inhibitory sVegfr1 results in the increased Dll4 expression and accelerated augmented coronary angiogenesis whereas blocking Notch signaling prohibits the process (not shown in the diagrams), suggesting that balanced Vegf and Notch signals collaborate in the endocardial cells to control the coronary angiogenesis.

Mentions: We have recently shown that the myocardial Vegfa to endocardial Vegfr2 signaling is essential for embryonic coronary angiogenesis by the progenitor cells within the endocardium to form the coronary arteries [33]. In this study using a conditional deletion strategy, we show that the endocardially-derived Vegfr1 is also required for normal coronary angiogenesis (Fig. 8A), it negatively regulates the process, possibly limiting the proangiogenic Vegf-Notch signaling.


Accelerated coronary angiogenesis by vegfr1-knockout endocardial cells.

Zhang Z, Zhou B - PLoS ONE (2013)

Working model shows the Vegf-Notch signaling in the ventricular endocardium that regulates coronary angiogenesis by the ventricular endocardial cells.A, Schematics showing that a balanced Vegf signaling in the endocardium (Control) is essential for the coronary angiogenesis by the ventricular endocardial cells. When the Vegf signaling in the endocardium is disrupted by deleting the proangiogenic Vegfr2 (R2 CKO) [27] or the anti-angiogenic Vegfr1 (R1 CKO; this study), the coronary angiogenesis is blocked or accelerated, respectively. B, Diagrams depicting a mode of controlled Vegf-Notch signaling that is necessary for normal coronary angiogenesis. Enhanced Vegf2 signaling in the endocardial cells by removal of the inhibitory sVegfr1 results in the increased Dll4 expression and accelerated augmented coronary angiogenesis whereas blocking Notch signaling prohibits the process (not shown in the diagrams), suggesting that balanced Vegf and Notch signals collaborate in the endocardial cells to control the coronary angiogenesis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3722158&req=5

pone-0070570-g008: Working model shows the Vegf-Notch signaling in the ventricular endocardium that regulates coronary angiogenesis by the ventricular endocardial cells.A, Schematics showing that a balanced Vegf signaling in the endocardium (Control) is essential for the coronary angiogenesis by the ventricular endocardial cells. When the Vegf signaling in the endocardium is disrupted by deleting the proangiogenic Vegfr2 (R2 CKO) [27] or the anti-angiogenic Vegfr1 (R1 CKO; this study), the coronary angiogenesis is blocked or accelerated, respectively. B, Diagrams depicting a mode of controlled Vegf-Notch signaling that is necessary for normal coronary angiogenesis. Enhanced Vegf2 signaling in the endocardial cells by removal of the inhibitory sVegfr1 results in the increased Dll4 expression and accelerated augmented coronary angiogenesis whereas blocking Notch signaling prohibits the process (not shown in the diagrams), suggesting that balanced Vegf and Notch signals collaborate in the endocardial cells to control the coronary angiogenesis.
Mentions: We have recently shown that the myocardial Vegfa to endocardial Vegfr2 signaling is essential for embryonic coronary angiogenesis by the progenitor cells within the endocardium to form the coronary arteries [33]. In this study using a conditional deletion strategy, we show that the endocardially-derived Vegfr1 is also required for normal coronary angiogenesis (Fig. 8A), it negatively regulates the process, possibly limiting the proangiogenic Vegf-Notch signaling.

Bottom Line: We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1- hearts.We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells.These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Biotherapy, West China Medical School of Sichuan University, Chengdu, Sichuan, China.

ABSTRACT
During mouse heart development, ventricular endocardial cells give rise to the coronary arteries by angiogenesis. Myocardially-derived vascular endothelial growth factor-a (Vegfa) regulates embryonic coronary angiogenesis through vascular endothelial growth factor-receptor 2 (Vegfr2) expressed in the endocardium. In this study, we investigated the role of endocardially-produced soluble Vegfr1 (sVegfr1) in the coronary angiogenesis. We deleted sVegfr1 in the endocardium of the developing mouse heart and found that this deletion resulted in a precocious formation of coronary plexuses. Using an ex vivo coronary angiogenesis assay, we showed that the Vegfr1- ventricular endocardial cells underwent excessive angiogenesis and generated extensive endothelial tubular networks. We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1- hearts. We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells. These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.

Show MeSH
Related in: MedlinePlus