Abstract
The mechanism of age‐related decline in the angiogenic potential of the myocardium is not yet fully understood. Our previous report revealed that the aging of cardiac microvascular endothelial cells (CMECs) led to changes in their expression of receptor Trk isoforms: among the three isoforms (TrkB‐FL, TrkB‐T1 and TrkB‐T2), only the truncated TrkB‐T1 isoform continued to be expressed in aged CMECs, which led to decreased migration of CMECs in aging hearts. Thus far, how BDNF induces signalling through the truncated TrkB‐T1 isoform in aged CMECs remains unclear. Here, we first demonstrated that aged CMECs utilize BDNF–TrkB‐T1 signalling to recruit Willin as a downstream effector to further activate the Hippo pathway, which then promotes migration. These findings suggest that the aging process shifts the phenotype of aged CMECs that express TrkB‐T1 receptors by transducing BDNF signals via the BDNF–TrkB‐T1–Willin–Hippo pathway and that this change might be an important mechanism and therapeutic target of the dysfunctional cardiac angiogenesis observed in aged hearts.
Highlights
Coronary artery disease‐induced myocardial infarction (MI) is one of the leading causes of morbidity and mortality among elderly individuals
Based on the TrkB‐T1 yeast two‐ hybrid screen with old rat cardiac microvascular endothelial cells (CMECs) cDNA and the observation that TrkB‐T1 interacted with Willin, we further proposed that the Brain‐ derived neurotrophic factor (BDNF)– TrkB‐T1 pathway might recruit Willin as a downstream effector to transduce BDNF signalling in old CMECs
The results revealed that the BDNF–TrkB‐T1–Willin pathway promoted the migration of old CMECs, and the increased migration effect in old CMECs after BDNF treatment was attributed to binding with TrkB‐T1 receptors, which led to the recruitment of the downstream effector, Willin
Summary
Coronary artery disease‐induced myocardial infarction (MI) is one of the leading causes of morbidity and mortality among elderly individuals. It is believed that endothelial cell aging shifts protective and angiogenic pathways, causing dysfunction in aged hearts, which may be an important aetiology of the age‐related decline in the regeneration of the myocardium and the poor cardiovascular prognoses observed in the elderly. Knowledge suggested that TrkB‐T1 is recognized as a dominant negative receptor that inhibits TrkB‐FL signalling, as it lacks the catalytic tyrosine kinase domain (Fenner, 2012) It remains to be determined how aged CMECs transduce BDNF signalling to regulate effects via the BDNF– TrkB‐T1 pathway under physiopathological situations. Aged CMECs might play a role in an unknown mechanism to transduce BDNF signals via the BDNF– TrkB‐T1 pathway to recruit unknown downstream effectors to maintain the angiogenic potential and capacity of the heart. We first report a novel mechanism by which aged CMECs expressing the TrkB‐T1 receptor isoform recruit Willin/FRMD6 as a downstream effector to activate the Hippo‐Yap pathway, transducing the BDNF signal to promote their migration
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