Connexin43 mRNA can be internally translated to generate N-terminally truncated isoforms including GJA1-20k. GJA1-20k expression is suppressed during TGF-β–induced epithelial–mesenchymal transition, stabilizing full-length Connexin43 in the Golgi, reducing channel oligomerization, cell surface expression, and connexin43 gap junction formation.

Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.

Eukaryotic mRNAs were historically thought to rely exclusively on recognition and binding of their 5’ cap by initiation factors to effect protein translation. While internal ribosome entry sites (IRESs) are well accepted as necessary for the cap-independent translation of many viral genomes, there is now recognition that eukaryotic mRNAs also undergo non-canonical modes of translation initiation. Recently, high-throughput assays have identified thousands of mammalian transcripts with translation initiation occurring at non-canonical start codons, upstream of and within protein coding regions. In addition to IRES-mediated events, regulatory mechanisms of translation initiation have been described involving alternate 5’ cap recognition, mRNA sequence elements, and ribosome selection. These mechanisms ensure translation of specific mRNAs under conditions where cap-dependent translation is shut down and contribute to pathological states including cardiac hypertrophy and cancer. Such global and gene-specific dynamic regulation of translation presents us with an increasing number of novel therapeutic targets. While these newly discovered modes of translation initiation have been largely studied in isolation, it is likely that several act on the same mRNA and exquisite coordination is necessary to maintain ‘normal’ translation. In this short review, we summarize the current state of knowledge of these alternative mechanisms of eukaryotic protein translation, their contribution to normal and pathological cell biology, and the potential of targeting translation initiation therapeutically in human disease.

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Graphical AbstractHighlights d In aged hearts and during hypoxia or TGF-b treatment, the GJA1 mRNA 5 0 UTR is truncated d Activation of P38 and ERK signal transduction pathways regulate GJA1 5 0 UTR length d Truncated GJA1 5 0 UTRs are sufficient to suppress internal translation of GJA1-20k d Reduced GJA1-20k expression is correlated with P38 activation in aged hearts

Myocardial ischemia leads to conduction slowing, cell-to-cell uncoupling, and arrhythmias. We previously demonstrated that varying perfusate sodium (Na+) and calcium (Ca2+) attenuates conduction slowing and arrhythmias during simulated ischemia with continuous perfusion. Cardioprotection was selectively associated with widening of the perinexus, a gap junction adjacent nanodomain important to ephaptic coupling. It is unknown whether perfusate composition affects the perinexus or ischemic conduction during non-simulated ischemia, when coronary flow is reduced or halted. We hypothesized that altering pre-ischemic perfusate composition could facilitate perinexal expansion and attenuate conduction slowing during global ischemia. To test this hypothesis, ex vivo guinea pig hearts (n=49) were Langendorff-perfused with 145 or 153mM Na+ and 1.25 or 2.0mM Ca2+, and optically mapped during 30 minutes of no-flow ischemia. Altering Na+ and Ca2+ did not significantly affect baseline conduction velocity (CV). Increasing Na+ and decreasing Ca2+ both lowered pacing thresholds, while increasing Ca2+ narrowed perinexal width (WP). A least squared means estimate revealed that reduced Na+ and Ca2+ slowed CV by 2.20 (cm/s)/min of ischemia. Increasing Ca2+ significantly attenuated CV slowing to 1.51 (cm/s)/min. Increasing Na+ attenuated CV slowing to 0.99 (cm/s)/min, and delayed median time to conduction block (10 to 16 minutes). Increasing Na+ and Ca2+ selectively widened WP during ischemia (22.7 vs 15.7nm) and attenuated CV slowing to the greatest extent (0.66 (cm/s)/min). Neither repolarization nor levels of total or phosphorylated connexin43 correlated with conduction slowing or block. Thus, perfusate-dependent widening of the perinexus preserved ischemic conduction and may be an adaptive response to ischemic stress.

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