The Role of Monocyte-Derived Cells and Inflammation in Baboon Ductus Arteriosus Remodeling

Abstract

Inflammatory processes play a crucial role in the pathogenesis of atherosclerosis and other vascular disorders. We hypothesized that ischemia of the ductus arteriosus might initiate an active inflammatory response that could play a role in ductus remodeling and permanent closure. To test this hypothesis, we studied effects of postnatal ductus construction on inflammatory processes and remodeling in late-gestation fetal and newborn baboons, and preterm newborn baboons. After postnatal ductus constriction, the expression of several genes known to be essential for atherosclerotic remodeling [vascular cell adhesion molecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-␥, IL-6, and tumor necrosis factor-␣] was increased in the ductus wall. We were unable to detect intercellular adhesion molecule (ICAM)-1, ICAM-2, Pselectin, monocyte chemoattractant protein-1, or IL-1 by either real-time PCR or immunohistochemistry. VCAM-1, which is newly expressed by luminal cells of the closed ductus, is an important ligand for the mononuclear cell adhesion receptor VLA4. After postnatal constriction, VLA4 ϩ monocytes/ macrophages (CD68 ϩ and CD14 ϩ ) and, to a lesser extent, T-lymphocytes adhered to the ductus wall. Neutrophils and platelets were not observed. The extent of postnatal neointimal remodeling (both endothelial cell layering and subendothelial space thickening) was associated with the degree of mononuclear cell adhesion. Similarly, the extent of vasa vasorum ingrowth correlated with the invasion of CD68 ϩ cells, from the adventitia into the muscle media. Based on these data, we conclude that the inflammatory response following postnatal ductus constriction may be as necessary for ductus remodeling as it is for atherosclerotic remodeling. Closure of the full-term ductus arteriosus occurs in two phases. First, smooth muscle constriction obstructs the ductus' lumen. Then, anatomic remodeling permanently occludes the lumen. The initial constriction appears to be the required stimulus for anatomic closure. During constriction, loss of luminal and vasa vasorum flow produce a zone of ischemichypoxia in the ductus' muscle media that induces the following anatomic changes: luminal endothelial proliferation, subendothelial thickening, ingrowth of vasa vasorum, and cell death (1). The preterm newborn is capable of remodeling its ductus, just like the full-term newborn, if it can impede its luminal flow and develop the same degree of ischemic-hypoxia as found at term (2).Although the cell death and ingrowth of vasa vasorum in the ductus wall appear to be due to ATP depletion (3,4) and VEGF induction (5), respectively, the mechanism(s) responsible for the neointimal changes are still unknown. It is now clear that inflammatory processes play a crucial role in the pathogenesis of several vascular disorders (6 -9). The most studied model of

Patent ductus arteriosus: pathophysiology and management

“…Several of these cytokines are potent vasodilators that act through mechanisms independent of either PGs or nitric oxide. 5 Another reason for the diminished contractile responsiveness of the ductus to indomethacin after birth has to do with energetics within the ductus wall. In the premature ductus, even when the lumen of the ductus remains patent, energy metabolites (i.e., glucose, oxygen, and ATP) begin to fall after birth.…”

Recent Advances Concerning the Molecular Mechanism of Patent Ductus Arteriosus

“…Clyman's group has demonstrated that the expression levels of vascular cell adhesion molecule (VCAM)-1 (an important ligand for the mononuclear cell adhesion receptor VLA4), E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-gamma, IL-6, and tumor necrosis factor-alpha are increased in the ductus wall. They have also found that VLA4+ monocytes/macrophages (CD68+ and CD14+) and, to a lesser extent, Tlymphocytes adhere to the postnatal DA (Waleh, 2005).…”

Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus

“…They found that VLA4 integrin expressing mononuclear cells (CD14 + /CD163 + cells [59]), in which the ligand is vascular cell adhesion molecule-1 (VCAM-1) in ECs, increased to adhere to the lumen of the DA after birth. Along with the increased monocytes recruitment, VCAM-1 and E-selectin expressions were also elevated in DA ECs after birth [58]. Unlike the pathophysiology of atherosclerosis, the upregulation of P-selectin and intracellular adhesion molecule-1 (ICAM-1) induced by monocytes adhesion was not seen in the DA.…”

“…+ mononuclear cell adhesion was found to predominantly regulate the extent of neointimal remodeling of the DA after birth, with T-lymphocyte adhesion to a lesser extent, but no neutrophil or platelet adhesion [58]. VCAM-1 and E-selectin were also induced by VEGF and several cytokines, such as TNF-α, IFN-γ, and CD154, likely due to the profound hypoxia in the DA wall after birth.…”

“…Therefore, ATP depletion causes cell death [55,56] and VEGF induction increases the penetration of vasa vasorum into the DA muscle media [57]. Clyman's group examined the inlammatory processes involved in the postnatal constriction of the DA [58]. They found that VLA4 integrin expressing mononuclear cells (CD14 + /CD163 + cells [59]), in which the ligand is vascular cell adhesion molecule-1 (VCAM-1) in ECs, increased to adhere to the lumen of the DA after birth.…”