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Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.

Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, Sweeney SM, Chen M, Guo L, Lu MM, Zhou D, Kitajewski J, Affolter M, Ginsberg MH, Kahn ML - Nat. Med. (2009)

Bottom Line: Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells.Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions.This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.

ABSTRACT
Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1(-/-) mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/lacZ) mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.

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Lymphatic vessel dilatation and leak in Heg1-/- neonates(a,b) HEG1-deficient neonates exhibit chylous ascites manifest by the accumulation of white chyle in the peritoneal space. (c-f) Lymphatic malformations in Heg1-/- animals. Neonatal mesenteric lymphatic vessels of Heg1-/- animals are dilated (arrows) and leak chyle into the intestinal wall as well as the peritoneum. Anti-LYVE1 immunostaining confirms the lymphatic identity of the dilated mesenteric vessels (arrows) (g,h). SMA, α-smooth muscle actin. Scale bars, 100 μm.
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Figure 2: Lymphatic vessel dilatation and leak in Heg1-/- neonates(a,b) HEG1-deficient neonates exhibit chylous ascites manifest by the accumulation of white chyle in the peritoneal space. (c-f) Lymphatic malformations in Heg1-/- animals. Neonatal mesenteric lymphatic vessels of Heg1-/- animals are dilated (arrows) and leak chyle into the intestinal wall as well as the peritoneum. Anti-LYVE1 immunostaining confirms the lymphatic identity of the dilated mesenteric vessels (arrows) (g,h). SMA, α-smooth muscle actin. Scale bars, 100 μm.

Mentions: Neonatal mammals transport absorbed fat through the intestinal and mesenteric lymphatic vessels in the form of white chyle. A distinct phenotype observed in HEG1-deficient neonates was the appearance of chylous ascites shortly after their first feeding (Fig. 2a,b). Chylous ascites was invariably associated with the presence of severely dilated intestinal and mesenteric lymphatic vessels that leaked chyle into the intestinal wall and peritoneal space (Fig. 2c-f). Dilated HEG1-deficient mesenteric lymphatics were lined with endothelial cells that expressed the lymphatic molecular marker LYVE1 and were associated with the smooth muscle cells typical of collecting lymphatics (Fig. 2g,h), but exhibited abnormal endothelial junctions and inter-endothelial cell gaps similar to those observed in human CCMs (Fig. 5). These findings demonstrate that loss of HEG1 receptors is associated with loss of integrity in lymphatic vessels as well as in the heart and blood vessels. Since lymphatic vessels are not subject to hemodynamic forces generated by the beating heart, these findings further suggest that loss of integrity can arise as an intrinsic defect in the cardiovascular organs of HEG1-deficient animals.


Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.

Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, Sweeney SM, Chen M, Guo L, Lu MM, Zhou D, Kitajewski J, Affolter M, Ginsberg MH, Kahn ML - Nat. Med. (2009)

Lymphatic vessel dilatation and leak in Heg1-/- neonates(a,b) HEG1-deficient neonates exhibit chylous ascites manifest by the accumulation of white chyle in the peritoneal space. (c-f) Lymphatic malformations in Heg1-/- animals. Neonatal mesenteric lymphatic vessels of Heg1-/- animals are dilated (arrows) and leak chyle into the intestinal wall as well as the peritoneum. Anti-LYVE1 immunostaining confirms the lymphatic identity of the dilated mesenteric vessels (arrows) (g,h). SMA, α-smooth muscle actin. Scale bars, 100 μm.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2665266&req=5

Figure 2: Lymphatic vessel dilatation and leak in Heg1-/- neonates(a,b) HEG1-deficient neonates exhibit chylous ascites manifest by the accumulation of white chyle in the peritoneal space. (c-f) Lymphatic malformations in Heg1-/- animals. Neonatal mesenteric lymphatic vessels of Heg1-/- animals are dilated (arrows) and leak chyle into the intestinal wall as well as the peritoneum. Anti-LYVE1 immunostaining confirms the lymphatic identity of the dilated mesenteric vessels (arrows) (g,h). SMA, α-smooth muscle actin. Scale bars, 100 μm.
Mentions: Neonatal mammals transport absorbed fat through the intestinal and mesenteric lymphatic vessels in the form of white chyle. A distinct phenotype observed in HEG1-deficient neonates was the appearance of chylous ascites shortly after their first feeding (Fig. 2a,b). Chylous ascites was invariably associated with the presence of severely dilated intestinal and mesenteric lymphatic vessels that leaked chyle into the intestinal wall and peritoneal space (Fig. 2c-f). Dilated HEG1-deficient mesenteric lymphatics were lined with endothelial cells that expressed the lymphatic molecular marker LYVE1 and were associated with the smooth muscle cells typical of collecting lymphatics (Fig. 2g,h), but exhibited abnormal endothelial junctions and inter-endothelial cell gaps similar to those observed in human CCMs (Fig. 5). These findings demonstrate that loss of HEG1 receptors is associated with loss of integrity in lymphatic vessels as well as in the heart and blood vessels. Since lymphatic vessels are not subject to hemodynamic forces generated by the beating heart, these findings further suggest that loss of integrity can arise as an intrinsic defect in the cardiovascular organs of HEG1-deficient animals.

Bottom Line: Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells.Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions.This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.

ABSTRACT
Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1(-/-) mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/lacZ) mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.

Show MeSH
Related in: MedlinePlus