Wnt7b regulates mesenchymal proliferation and vascular development in the lung

Development ◽  
2002 ◽  
Vol 129 (20) ◽  
pp. 4831-4842 ◽  
Author(s):  
Weiguo Shu ◽  
Yue Qin Jiang ◽  
Min Min Lu ◽  
Edward E. Morrisey
Keyword(s):  
Smooth Muscle ◽  
Airway Epithelium ◽  
Lung Development ◽  
Perinatal Death ◽  
Vascular Development ◽  
Wnt Signaling Pathway ◽  
Lung Hypoplasia ◽  
Coding Region ◽  
Newborn Mice ◽  
Pulmonary Vessels

Although the Wnt signaling pathway regulates inductive interactions between epithelial and mesenchymal cells, little is known of the role that this pathway plays during lung development. Wnt7b is expressed in the airway epithelium, suggesting a possible role for Wnt-mediated signaling in the regulation of lung development. To test this hypothesis, we have mutated Wnt7b in the germline of mice by replacement of the first exon with the lacZ-coding region. Wnt7blacZ–/– mice exhibit perinatal death due to respiratory failure. Defects in early mesenchymal proliferation leading to lung hypoplasia are observed in Wnt7blacZ–/– embryos. In addition, Wnt7blacZ–/– embryos and newborn mice exhibit severe defects in the smooth muscle component of the major pulmonary vessels. These defects lead to rupture of the major vessels and hemorrhage in the lungs after birth. These results demonstrate that Wnt7b signaling is required for proper lung mesenchymal growth and vascular development.

Defective vascular development in connexin 45-deficient mice

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4179-4193 ◽  
Author(s):  
O. Kruger ◽  
A. Plum ◽  
J.S. Kim ◽  
E. Winterhager ◽  
S. Maxeiner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Reporter Gene ◽  
Vascular Development ◽  
Subsequent Development ◽  
Yolk Sac ◽  
Abnormal Development ◽  
Coding Region ◽  
Junction Protein ◽  
Visceral Smooth Muscle ◽  
Deficient Mice

In order to reveal the biological function(s) of the gap-junction protein connexin 45 (Cx45), we generated Cx45-deficient mice with targeted replacement of the Cx45-coding region with the lacZ reporter gene. Heterozygous Cx45(+/)(−) mice showed strong expression of the reporter gene in vascular and visceral smooth muscle cells. Cx45-deficient embryos exhibited striking abnormalities in vascular development and died between embryonic day (E) 9.5 and 10.5. Differentiation and positioning of endothelial cells appeared to be normal, but subsequent development of blood vessels revealed impaired formation of vascular trees in the yolk sac, impaired allantoic mesenchymal ingrowth and capillary formation in the labyrinthine part of the placenta, and arrest of arterial growth, including a failure to develop a smooth muscle layer surrounding the major arteries of the embryo proper. As a consequence, the hearts of most Cx45-deficient embryos were dilated. The abnormal development of the vasculature in the yolk sac of Cx45(−)(/)(−) embryos could be caused by defective TGFbeta signalling, as the amount of TGF beta1 protein in the epithelial layer of the yolk sac was largely decreased in the E9.5 Cx45(−)(/)(−) embryo, compared with the wild-type embryo. The defective vascular development was accompanied by massive apoptosis, which began in some embryos at E8.5 and was abundant in virtually all tissues of the embryos at E9.5. We conclude that in Cx45(−)(/)(−) embryos, vasculogenesis was normal, but subsequent transformation into mature vessels was interrupted. Development of different types of vessels was impaired to a varying extent, which possibly reflects the complementation by other connexin(s).

scholarly journals Wnt7b Activates Canonical Signaling in Epithelial and Vascular Smooth Muscle Cells through Interactions with Fzd1, Fzd10, and LRP5

2005 ◽  
Vol 25 (12) ◽  
pp. 5022-5030 ◽  
Author(s):  
Zhishan Wang ◽  
Weiguo Shu ◽  
Min Min Lu ◽  
Edward E. Morrisey
Keyword(s):  
Cell Surface ◽  
Wnt Signaling ◽  
Airway Epithelium ◽  
Lung Development ◽  
Wnt Pathway ◽  
Vascular Development ◽  
Placental Development ◽  
Surface Receptors ◽  
Wnt Ligands ◽  
Canonical Wnt

ABSTRACT Wnt7b is a Wnt ligand that has been demonstrated to play critical roles in several developmental processes, including lung airway and vascular development and chorion-allantois fusion during placental development. Wnt signaling involves the binding of Wnt ligands to cell surface receptors of the frizzled family and coreceptors of the LRP5/6 family. However, little is known of the ligand-receptor specificity exhibited by different Wnts, Fzds, and LRPs in Wnt signaling. Expression analysis of Fzds and LRP5/6 in the developing lung and vasculature showed that Fzd1, -4, -7, and -10 and LRP5/6 are expressed in tissue-specific patterns during lung development. Fzd1, -4, and -7 are expressed primarily in the developing lung mesenchyme, and Fzd10 is expressed in airway epithelium. LRP5 and LRP6 are expressed in airway epithelium during lung development, whereas LRP5 but not LRP6 expression is observed in the muscular component of large blood vessels, including the aorta. Cell transfection studies demonstrate that Wnt7b can activate the canonical Wnt pathway but not the noncanonical Wnt pathway in a cell-specific manner. Biochemical analysis demonstrates that Wnt7b can bind to Fzd1 and -10 on the cell surface and cooperatively activate canonical Wnt signaling with these receptors in the presence of LRP5. Together, these data demonstrate that Wnt7b signals through Fzd1 and -10 and LRP5 and implicate these Wnt coreceptors in the regulation of lung airway and vascular development.

The role of WNT/b-catenin signaling in smooth muscle cells during lung development and repair

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
A Moiseenko ◽  
E El Agha ◽  
B MacKenzie ◽  
S De Langhe ◽  
S Bellusci
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Lung Development ◽  
Muscle Cells

Cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-β1 and reactive oxygen species: a requirement for NAD(P)H oxidase

2005 ◽  
Vol 289 (2) ◽  
pp. L288-L289 ◽  
Author(s):  
Eugenia Mata-Greenwood ◽  
Albert Grobe ◽  
Sanjiv Kumar ◽  
Yelina Noskina ◽  
Stephen M. Black
Keyword(s):  
Reactive Oxygen Species ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Reactive Oxygen ◽  
Cyclic Stretch ◽  
Oxygen Species ◽  
Vegf Expression ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial ◽  
Tgf Β1

Our previous studies have indicated that transforming growth factor (TGF)-β1 and VEGF expression are increased in the smooth muscle cell (SMC) layer of the pulmonary vessels of lambs with pulmonary hypertension secondary to increased pulmonary blood flow. Furthermore, we found that TGF-β1 expression increased before VEGF. Because of the increased blood flow in the shunt lambs, the SMC in the pulmonary vessels are exposed to increased levels of the mechanical force, cyclic stretch. Thus, in this study, using primary cultures of pulmonary arterial SMC isolated from pulmonary arteries of 4-wk-old lambs, we investigated the role of cyclic stretch in the apparent coordinated regulation of TGF-β1 and VEGF. Our results demonstrated that cyclic stretch induced a significant increase in VEGF expression both at the mRNA and protein levels ( P < 0.05). The increased VEGF mRNA was preceded by both an increased expression and secretion of TGF-β1 and an increase in reactive oxygen species (ROS) generation. In addition, a neutralizing antibody against TGF-β1 abolished the cyclic stretch-dependent increases in both superoxide generation and VEGF expression. Our data also demonstrated that cyclic stretch activated an NAD(P)H oxidase that was TGF-β1 dependent and that NAD(P)H oxidase inhibitors abolished the cyclic stretch-dependent increase in VEGF expression. Therefore, our results indicate that cyclic stretch upregulates VEGF expression via the TGF-β1-dependent activation of NAD(P)H oxidase and increased generation of ROS.

Abstract 312: Jagged1 and Morphological Integrity of the Kidney

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Brian C Belyea ◽  
Fang Yu ◽  
Maria Luisa S Sequeira-Lopez ◽  
R. Ariel Gomez
Keyword(s):  
Smooth Muscle ◽  
Mesangial Cells ◽  
Interstitial Fibrosis ◽  
Vascular Development ◽  
Critical Role ◽  
Precursor Cells ◽  
Conditional Knockout ◽  
Kidney Cortex ◽  
Fibrotic Process ◽  
Renal Vascular

Renal vascular development is dependent on the participation of renin precursor cells, which localize to areas of new vessel formation and differentiate into smooth muscle cells (SMCs), mesangial and juxtaglomerular (JG) cells. However, the mechanisms that enforce this particular fate of renin precursor cells remain unclear. During embryogenesis, renin cells express a significant number of angiogenic factors including the Notch signaling ligand Jagged1. We therefore hypothesized that Jagged1 is necessary for renin precursors to differentiate into the various mural cells of the renal arterioles and that Jagged1 plays a critical role in renal vascular development. To generate conditional Jagged1 deletion in cells of the renin lineage, we crossed Jagged1 fl/fl mice with Ren1d cre/+ mice. We investigated kidney weight, morphology, and vascular architecture as well as the identity of cells composing the kidney arterioles including renin cells and SMCs. We performed quantitative RT-PCR on kidney cortex mRNA for Jagged1 and Renin expression levels and immunohistochemistry for renin. The expression of Jagged1 mRNA in conditional knockout (cKO) animals was reduced at 2 weeks (68.3% reduction) and 4 weeks (66.5% reduction) compared to control mice. We found no significant differences between control and cKO animals in their kidney weights, renin mRNA expression, and renin staining. The number of renin-positive juxtaglomerular apparatuses (JGA) was 49.25 +/- 3.301 (n=4) and 38.00 +/- 4.830 (n=4) for control and cKO mice respectively under physiologic conditions. Staining for α-smooth muscle actin (α-SMA) demonstrated an overall normal vascular anatomy in cKO kidneys, however there were focal areas containing activated pericytes and injured mesangial cells expressing α-SMA indicating an active fibrotic process. Mason’s trichrome staining confirmed areas of glomerular and interstitial fibrosis in cKO kidneys. This work suggests that while Jagged1 is dispensable for renin expression, its loss in renin cell descendants affects perivascular-interstitial integrity and glomerular structure. The findings indicate an important role of Jagged1 in the maintenance of the morphologic integrity of the kidney.

The Effects of Extracellular Matrix Protein Insufficiency and Treatment on the Stiffness of Arterial Smooth Muscle Cells

2013 ◽  
Author(s):  
Gabriela Espinosa ◽  
Lisa Bennett ◽  
William Gardner ◽  
Jessica Wagenseil
Keyword(s):  
Mechanical Properties ◽  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Elastic Tissue ◽  
Newborn Mice ◽  
Ecm Proteins ◽  
Wall Stiffness ◽  
Deficient Mice

Increased arterial stiffness is directly correlated with hypertension and cardiovascular disease. Stiffness of the conducting arteries is largely determined by the extracellular matrix (ECM) proteins in the wall, such as collagen and elastin, produced by the smooth muscle cells (SMCs) found in the medial layer. Elastin is deposited as soluble tropoelastin and is later crosslinked into elastin fibers. Newborn mice lacking the elastin protein ( Eln−/−) have increased arterial wall stiffness and SMCs with altered proliferation, migration and morphology [1]. Vessel elasticity is also mediated by other ECM proteins, such as fibulin-4. Elastic tissue, such as lung, skin, and arteries, from fibulin-4 deficient ( Fbln4−/−) mice show no decrease in elastin content, but have reduced elasticity due to disrupted elastin fibers [2]. Arteries from both elastin and fibulin-4 deficient mice have been previously studied, but the mechanical properties of their SMCs have not been investigated. Recent experiments comparing arterial SMCs from old and young animals suggest that mechanical properties of the SMCs themselves may contribute to changes in wall stiffness [3]. Hence, we investigated the stiffness of isolated arterial SMCs from elastin and fibulin-4 deficient mice using atomic force microscopy (AFM). In addition, we studied the effects of two elastin treatments on the mechanical properties of SMCs from Eln+/+ and Eln−/− mice. Differences between the treatments may elucidate the importance of soluble versus crosslinked elastin on single cell stiffness.

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