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    • br Angiogenic and vasculogenic responses during heart regene

    2018-11-06


    Angiogenic and vasculogenic responses during heart regeneration Re-establishment of a new vasculature following cardiac injury is vital for heart regeneration. In neonatal mice, large epicardial blood vessels are evident in the regenerated heart following apical resection injury (Porrello et al., 2011a). Recent studies also indicate that cardiac regeneration following neonatal myocardial infarction is associated with a robust vasculogenic response with large collateral vessels penetrating the infarcted territory during regeneration (Porrello et al., 2013). In contrast, a similar vascular injury response is not evident in adult rodents, suggesting that important developmental differences in the reparative potential of vascular order diprenorphine may contribute to the loss of cardiac regenerative capacity during the neonatal period. Two of the most important pro-angiogenic factors during zebrafish heart regeneration are Fgf and Pdgf (Fig. 2). Following apical resection injury, Fgf ligands, such as fgf17b, are up-regulated in the myocardium, while the Fgf receptors fgfr2 and fgfr4 are induced in epicardial cells (Lepilina et al., 2006). Transgenic loss-of-function studies in the zebrafish have established that Fgf receptor expression in epicardial cells is required for epicardial cell invasion into the wound site and neovascularization. In the absence of Fgf receptor-dependent neovascularization, the zebrafish heart fails to regenerate following injury and forms a large fibrotic scar (Lepilina et al., 2006). Similarly, Pdgf signaling is also required for epicardial cell proliferation and blood vessel formation following cardiac injury in zebrafish. The PDGF receptor alpha (pdgfrα) gene is up-regulated in epicardial cells and at the wound site following apical resection injury, while the PDGF-B ligand is expressed locally in the wound site by CD41-positive thrombocytes (Kim et al., 2010; Lien et al., 2006). Pharmacological inhibition of Pdgf signaling inhibits neovascularization following apical resection injury (Kim et al., 2010). These findings have established an important myo-epicardial growth factor signaling nexus during cardiac regeneration and it will be important to establish whether these signaling pathways are also activated during neonatal heart regeneration in mammals. Given the exciting recent developments in modified RNA-based delivery methods for angiogenic growth factors, such as vascular endothelial growth factor (VEGF) (Zangi et al., 2013), it may be possible to recapitulate some of these pro-regenerative and pro-angiogenic signaling pathways in the adult heart in the future.
    The extracellular matrix facilitates cardiac regeneration The predominant reparative response to cardiac injury in adult mammals involves the replacement of damaged myocardial tissue with a permanent collagenous scar. Cardiac fibroblasts account for up to two thirds of all cardiac cells and are embedded within the extracellular matrix (ECM) where they secrete the collagens required for matrix synthesis, as well as growth factors that support cardiomyocyte function and remodeling (Porter and Turner, 2009). In contrast to the fibrotic response of the adult heart following infarction, the neonatal heart does not form a stable fibrotic scar. However, there is considerable ECM deposition during the first week following cardiac injury in neonatal mice (Porrello et al., 2011a; Porrello et al., 2013). Subsequently, the fibrotic tissue becomes marginalized to the periphery and regresses over several weeks before being almost completely replaced with regenerated cardiomyocytes (Porrello et al., 2013). In the absence of an adequate myocyte proliferative response in the neonate, the default repair response is characterized by the presence of a fibrotic scar (Porrello et al., 2013; Xin et al., 2013; Mahmoud et al., 2013). These findings suggest that there is a reciprocal relationship between cardiomyocyte proliferation and fibrosis. Although little is known about the communication between fibroblasts and cardiomyocytes at early developmental stages, there is some evidence that cardiac fibroblasts regulate myocardial proliferation during embryogenesis. For example, fibronectin, collagen and heparin-binding EGF-like growth factor are all produced by embryonic cardiac fibroblasts and can promote proliferation of immature cardiomyocytes (Ieda et al., 2009). These proliferative effects are dependent on the expression of the ECM receptor, β1 integrin, in cardiomycytes. Interestingly, the expression of different integrin subunits (e.g. Itga1, Itgb1, Itga6 and Itga7), which have varying propensities to bind to different ECM components (e.g. collagen, laminin, fibronectin), changes during cardiomyocyte maturation (Ieda et al., 2009). It is therefore possible that postnatal changes in the ECM contribute to cardiomyocyte cell cycle withdrawal during the neonatal period. Furthermore, as re-establishment of the ECM is important for heart regeneration, further studies will be required in order to determine whether ECM components provide integral signals for neonatal heart regeneration.