Cell-extracellular matrix interactions in the ductus arteriosus and perinatal pulmonary circulation

doi:10.1016/S0146-0005(96)80067-X

Seminars in Perinatology

Volume 20, Issue 6, December 1996, Pages 531-541

https://doi.org/10.1016/S0146-0005(96)80067-X Get rights and content

Our studies and those of others have shown that changes in the extracellular matrix have profound effects on vascular remodeling. In the ductus, increased production of endothelial hyaluronan and smooth muscle cell chondroitin sulfate and fibronectin and impaired elastin fiber assembly are features critical to smooth muscle cell migration into the subendothelium and intimal cushion formation. There is a developmentally orchestrated process that involves post-transcriptional mechanisms of gene regulation. Closure of the ductus arteriosus is associated with further changes in matrix expression and programed cell death. The changes in the extracellular matrix that induce neointimal formation are also observed in pathological conditions in pulmonary and coronary arteries. Plasticity of the pulmonary circulation in the perinatal period also involves matrix regulation, and processes that prevent the normal decrease in pulmonary vascular resistance will result in impaired matrix regulation, and in the development of structural changes in the pulmonary arteries, including abnormal smooth muscle cell differentiation, hypertrophy and proliferation, which sustain the elevation in pulmonary artery pressure.

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The ductus arteriosus (DA), an essential fetal shunt between the pulmonary trunk and the descending aorta, changes its structure during development. Our previous studies have demonstrated that prostaglandin E₂ (PGE₂)-EP4 signaling promotes intimal cushion formation (ICF) by activating the migration of DA smooth muscle cells via the secretion of hyaluronan. We hypothesized that, in addition to hyaluronan, PGE₂ may secrete other proteins that also regulate vascular remodeling in the DA. In order to detect PGE₂ stimulation-secreted proteins, we found that CCN3 protein was increased in the culture supernatant in the presence of PGE₂ in a dose-dependent manner by nano-flow liquid chromatography coupled with tandem mass spectrometry analysis and enzyme-linked immunosorbent assay. Quantitative RT-PCR analysis revealed that PGE₂ stimulation tended to increase the expression levels of CCN3 mRNA in DA smooth muscle cells. Immunohistochemical analysis revealed that CCN3 was highly localized in the entire smooth muscle layers and the endothelium of the DA. Furthermore, exogenous CCN3 inhibited PGE₂-induced ICF in the ex vivo DA tissues. These results suggest that CCN3 is a secreted protein of the DA smooth muscle cells induced by PGE₂ to suppress ICF of the DA. The present study indicates that CCN3 could be a novel negative regulator of ICF in the DA to fine-tune the PGE₂-mediated DA remodeling.
Circulatory changes associated with the closure of the ductus arteriosus in hatching emu (Dromaius novaehollandiae)
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In developing avian embryos, the right and left ductus arteriosi (DA) allow for a shunt of systemic venous return away from the lungs to the body and chorioallantoic membrane (CAM). Unlike in mammals where the transition from placental respiration to lung respiration is instantaneous, in birds the transition from embryonic CAM respiration to lung respiration can take over 24 h. To understand the physiological consequences of this long transition we examined circulatory changes and DA morphological changes during hatching in the emu (Dromaius novaehollandiae), a primitive ratite bird. By tracking microspheres injected into a CAM vein, we observed no change in DA blood flow between the pre-pipped to internally pipped stages. Two hours after external pipping, however, a significant decrease in DA blood flow occurred, evident from a decreased systemic blood flow and subsequent increased lung blood flow. Upon hatching, the right-to-left shunt disappeared. These physiological changes in DA blood flow correspond with a large decrease in DA lumen diameter from the pre-pipped stages to Day 1 hatchlings. Upon hatching, the right-to-left shunt disappeared and at the same time apoptosis of smooth muscle cells began remodeling the DA for permanent closure. After the initial smooth muscle contraction, the lumen disappeared as intimal cushioning formed, the internal elastic lamina degenerated, and numerous cells underwent regulated apoptosis. The DA closed rapidly between the initiation of external pipping and hatching, resulting in circulatory patterns similar to the adult. This response is most likely produced by increased DA constriction in response to increased arterial oxygen levels and the initiation of vessel remodeling.
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By using gradient ionic detergent, we completed the decellularization process in approximately 5 h, which was shorter than >10 hours in previous experiments (p < 0.001). The extracellular matrix was kept relatively intact, with no obvious inflammatory cellular infiltration or structural damage in the grafted tissue. The engraftment efficiencies of HepG2 were 86 ± 5% (n = 8). The levels of albumin and urea synthesis were significantly superior to the ones in traditional two-dimensional culture.
The current new method can be used efficiently for the decellularization of the liver biologic scaffold with satisfying biocomparability for application both in vivo and in vitro.
T-type Ca<sup>2+</sup> channels promote oxygenation-induced closure of the rat ductus arteriosus not only by vasoconstrictionbut also by neointima formation
2009, Journal of Biological Chemistry
Citation Excerpt :
These data may explain the association between the up-regulation of α1G in the rat neonatal DA and an increase in oxygen tension in the circulation after birth. Progressive SMC migration from vascular media into the endothelial layer is an important vascular remodeling process of the DA at birth (1, 19, 23). These findings regarding the localization of α1G protein that was observed suggest that α1G regulated the SMC migration of the DA.
The ductus arteriosus (DA), an essential vascular shunt for fetal circulation, begins to close immediately after birth. Although Ca²⁺ influx through several membrane Ca²⁺ channels is known to regulate vasoconstriction of the DA, the role of the T-type voltage-dependent Ca²⁺ channel (VDCC) in DA closure remains unclear. Here we found that the expression of α1G, a T-type isoform that is known to exhibit a tissue-restricted expression pattern in the rat neonatal DA, was significantly up-regulated in oxygenated rat DA tissues and smooth muscle cells (SMCs). Immunohistological analysis revealed that α1G was localized predominantly in the central core of neonatal DA at birth. DA SMC migration was significantly increased by α1G overexpression. Moreover, it was decreased by adding α1G-specific small interfering RNAs or using R(−)-efonidipine, a highly selective T-type VDCC blocker. Furthermore, an oxygenation-mediated increase in an intracellular Ca²⁺ concentration of DA SMCs was significantly decreased by adding α1G-specific siRNAs or using R(−)-efonidipine. Although a prostaglandin E receptor EP4 agonist potently promoted intimal thickening of the DA explants, R(−)-efonidipine (10⁻⁶m) significantly inhibited EP4-promoted intimal thickening by 40% using DA tissues at preterm in organ culture. Moreover, R(−)-efonidipine (10⁻⁶m) significantly attenuated oxygenation-induced vasoconstriction by ∼27% using a vascular ring of fetal DA at term. Finally, R(−)-efonidipine significantly delayed the closure of in vivo DA in neonatal rats. These results indicate that T-type VDCC, especially α1G, which is predominantly expressed in neonatal DA, plays a unique role in DA closure, implying that T-type VDCC is an alternative therapeutic target to regulate the patency of DA.
Pathophysiology of patent ductus arteriosus in premature neonates
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Failure of complete postnatal closure of the ductus arteriosus is associated with various neonatal morbidities. Functional closure resulting from smooth muscle constriction and permanent anatomic closure due to vascular remodeling are the results of a complex interaction of different mechanisms. Prostaglandins, oxygen, nitric oxide and various other factors play a key role in ductal closure. An understanding of the role of these factors, involved both in maintenance of vascular tone of the ductus in fetal life as well as stimulation of ductal closure in postnatal life, and the cardiovascular and respiratory consequences of a patent ductus arteriosus, is important for the clinician involved in management of premature neonates.
Prostaglandin E<inf>2</inf>-activated Epac promotes neointimal formation of the rat ductus arteriosus by a process distinct from that of cAMP-dependent protein kinase A
2008, Journal of Biological Chemistry
Citation Excerpt :
Along this line, we found that Epac activated Rap1 (Fig. 2) and focal adhesion (Fig. 5) in DA SMCs. Since fibronectin plays a critical role in promoting migration of DA SMCs (16), our data suggested that a Rap1-mediated increase in cell adhesion to fibronectin is responsible, at least in part, for Epac-promoted SMC migration. Until now, the functional differences between Epac1 and Epac2 have not been fully understood.
We have demonstrated that chronic stimulation of the prostaglandin E₂-cAMP-dependent protein kinase A (PKA) signal pathway plays a critical role in intimal cushion formation in perinatal ductus arteriosus (DA) through promoting synthesis of hyaluronan. We hypothesized that Epac, a newly identified effector of cAMP, may play a role in intimal cushion formation (ICF) in the DA distinct from that of PKA. In the present study, we found that the levels of Epac1 and Epac2 mRNAs were significantly up-regulated in the rat DA during the perinatal period. A specific EP4 agonist, ONO-AE1-329, increased Rap1 activity in the presence of a PKA inhibitor, PKI-(14-22)-amide, in DA smooth muscle cells. 8-pCPT-2′-O-Me-cAMP (O-Me-cAMP), a cAMP analog selective to Epac activator, promoted migration of DA smooth muscle cells (SMC) in a dose-dependent manner. Adenovirus-mediated Epac1 or Epac2 gene transfer further enhanced O-Me-cAMP-induced cell migration, although the effect of Epac1 overexpression on cell migration was stronger than that of Epac2. In addition, transfection of small interfering RNAs for Epac1, but not Epac2, significantly inhibited serum-mediated migration of DA SMCs. In the presence of O-Me-cAMP, actin stress fibers were well organized with enhanced focal adhesion, and cell shape was widely expanded. Adenovirus-mediated Epac1, but not Epac2 gene transfer, induced prominent ICF in the rat DA explants when compared with those with green fluorescent protein gene transfer. The thickness of intimal cushion became significantly greater (1.98-fold) in Epac1-overexpressed DA. O-Me-cAMP did not change hyaluronan production, although it decreased proliferation of DA SMCs. The present study demonstrated that Epac, especially Epac1, plays an important role in promoting SMC migration and thereby ICF in the rat DA.

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View full text

Cell-extracellular matrix interactions in the ductus arteriosus and perinatal pulmonary circulation

J Pediatr

J Am Coll Cardiol

J Biol Chem

Exp Cell Res

Dev Biol

Atherosclerosis

Exp Cell Res

Ches

Further evidence implicating a cytochrome P-450-mediated reaction to the contractile tension of the lamb ductus arteriosus

Circ Res

Endothelin-1 release from lamb ductus arteriosus: Relevance to postnatal closure of the vessel

Can J Physiol Pharmacol

Histology of the persistent ductus arteriousus in case of congenital rubella

Circulation

Transforming growth factor-β regulates increased ductus arteriosus endothelial glycosaminoglycan synthesis and a post-transcriptional mechanism controls increased smooth muscle fibronectin, features associated with intimal proliferation

Lab Invest

Developmentally regulated expression of transforming growth factor β1 in the ductus arteriosus related to the formation of intimal cushions

Mol Cell Biol

Developmentally regulated changes in extracellular matrix in endothelial and smooth muscle cells in the ductus arteriosus may be related to intimal proliferation

Lab Invest

Transforming growth factor-β protein and messenger RNA expression is increased in the closing ductus arteriosus

Pediatr Res

Changes in endothelial cell and smooth muscle cell integrin expression during closure of the ductus arteriosus: An immunohistochemical comparison of the fetal, preterm newborn, and full-term newborn rhesus monkey ductus

Pediatr Res

Ductus arteriosus smooth muscle cell migration on collagen dependence on laminin and its receptors

J Cell Sci

Endogenous retinoic acid signaling colocalizes with advanced expression of the adult smooth muscle myosin heavy chain isoform during development of the ductus arteriosus

Circ Res

Impaired elastin fiber assembly related to reduced 67-kD elastin-binding protein in fetal lamb ductus arteriosus and cultured aortic smooth muscle cells treated with chondroitin sulfate

J Clin Invest

A developmentally regulated program restricting insolubilization of elastin and formation of laminae in the fetal lamb ductus arteriosus

Lab Invest

The 67-kD elastin/laminin-binding protein is related to an enzymatically inactive, alternatively spliced from of β-galactosidase

J Clin Invest

67-kD elastin-binding protein is a protective “companion” of extracellular insoluble elastin and intracellular tropoelastin

J Cell Biol