Cerebral cavernous malformation is a clinically well-defined microvascular disorder predisposing to stroke; however, the major phenotype observed in zebrafish is the cardiac defect, specifically an enlarged heart. Less effort has been made to explore this phenotypic discrepancy between human and zebrafish. Given the fact that the gene products from Ccm1/Ccm2 are nearly identical between the two species, the common sense has dictated that the zebrafish animal model would provide a great opportunity to dissect the detailed molecular function of Ccm1/Ccm2 during angiogenesis. We recently reported on the cellular role of the Ccm1 gene in biochemical processes that permit proper angiogenic microvascular development in the zebrafish model. In the course of this experimentation, we encountered a vast amount of recent research on the relationship between dysfunctional angiogenesis and cardiovascular defects in zebrafish. Here we compile the findings of our research with the most recent contributions in this field and glean conclusions about the effect of defective angiogenesis on the developing cardiovascular system. Our conclusion also serves as a bridge for the phenotypic discrepancy between humans and animal models, which might provide some insights into future translational research on human stroke.
Macrophages play key role in initial tissue remodeling by engulfing debris and releasing cytokines at the site of injury. Currently, the contribution of macrophage PPARγ in response to myocardial infarction (MI) and post‐MI remodeling is unknown and the effect of early cytokine signals on the post‐MI expression of collagens, MMPs (Matrix metalloproteinases) and TIMPs (tissue inhibitors of MMP) is unclear. The study objective was to examine the role of macrophage PPARγ in post‐MI remodeling, particularly collagen I & III, MMP, and TIMP expression using macrophage specific PPARγ knockout (KO) and wild type (WT) mice. Protein and RNA were extracted from 28‐day post‐MI heart tissues from WT and PPARγ‐KO mice for western blot and real‐time PCR analysis. qPCR results showed a significant increase (p<0.05) in expression of collagens I and III, MMPs 9 and 13, and TIMPs 1 and 2 in the 28‐day post‐MI PPARγ‐KO model compared to the WTMI group. The level of MMP 2, although not significantly elevated, showed an increasing trend in the PPARγ‐KOMI compared to WTMI group. Western blot showed similar increasing trends in TIMP 1 and 2 expressions in the PPARγ‐KOMI group. Our results indicate that PPARγ could be influencing the initial signals that alter post‐MI remodeling by regulating the expression of collagens (I, III), MMP 9, TIMPs 1 and 2.
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