The Cardiovascular Triad of Dysfunctional Angiogenesis

Abstract

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.

Release of Full-Length PrPC from Cultured Neurons Following Neurotoxic Challenges

“…Although the release of PrP C in response to neurotoxin challenge in vitro is interesting and may offer some insight as to its neuroprotective mechanism, its ability to serve a similar function and/or as a CNS biomarker following brain insult is attractive but speculative and requires further investigation. The release of proteins (e.g., SBDPs, UCH-L1) from neuronal cultures subjected to neurotoxic challenges have not only been reported previously (Dutta et al, 2002; Siman et al, 2004) but have also proven to be useful CNS biomarkers after traumatic or ischemic brain injury (Zhang et al, 2011). …”

Recent advances in cerebral cavernous malformation research

“…CCM2 is found ubiquitously expressed in the endothelial cells (EC) from various organs [55,56] . Despite the lack of a recognizable NLS and NES, CCM2 is found in both the nucleus and cytoplasm due to its interaction with CCM1 [18,23,57] . In the absence of functional CCM1, CCM2 is not localized to the cell junction, however, this function is recovered with the addition of wild-type CCM1, implying that binding to CCM1 is essential for localization of CCM2 to the cell junction [58] .…”

“…β1-integrin signaling is an important regulator in many cellular functions such as cellular migration and adhesion [15,24,25,57] . These functions are especially important for EC cells.…”

“…Our previous results indicate that CCM1 binds to ICAP1α and modulates ICAP1α and β1-integrin interaction. Depletion of CCM1 and ICAP1α synergistically inhibits extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase pathway activation on cell survival [15,23–25,57,72] . We hypothesized that CCM1 regulated recruitment of ICAP1α to the cell membrane in proximity to focal adhesions, which may be critical for the maintenance of cellular architecture as well as regulation of β1-integrin-mediated signaling [25] .…”

Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers

“…CCM proteins have been demonstrated to play major roles in microvascular angiogenesis in human and animal models (1)(2)(3)(4)(5)(6), which is an essential step for cancer growth during tumorigenesis (5,6). Three genes have been identified as causes of CCMs: cerebral cavernous malformations 1 [(CCM1) also termed Krev interaction trapped 1 (KRIT1)], cerebral cavernous malformation 2 [(CCM2) also termed MGC4607] and cerebral cavernous malformation 3 [(CCM3) also termed programmed cell death 10 (PDCD10)].…”