Heart failure impairs the mechanotransduction properties of human cardiac pericytes

Abstract

The prominent impact that coronary microcirculation disease (CMD) exerts on heart failure symptoms and prognosis, even in the presence of macrovascular atherosclerosis, has been recently acknowledged. Experimental delivery of pericytes in non-revascularized myocardial infarction improves cardiac function by stimulating angiogenesis and myocardial perfusion.Aim of this work is to verify if pericytes (Pc) residing in ischemic failing human hearts display altered mechano-transduction properties and to assess which alterations of the mechano-sensing machinery are associated with the observed impaired response to mechanical cues. Results: Microvascular rarefaction and defects of YAP/TAZ activation characterize failing human hearts. Although both donor (D-) and explanted (E-) heart derived cardiac Pc support angiogenesis, D-Pc exert this effect significantly better than E-Pc. The latter are characterized by reduced focal adhesion density, decreased activation of the focal adhesion kinase (FAK)/ Crk-associated substrate (CAS) pathway, low expression of caveolin-1, and defective transduction of extracellular stiffness into cytoskeletal stiffening, together with an impaired response to both fibronectin and lysophosphatidic acid. Importantly, Mitogen-activated protein kinase kinase inhibition restores YAP/TAZ nuclear translocation. Conclusion: Heart failure impairs Pc mechano-transduction properties, but this defect could be reversed pharmacologically.

Validation of Specific and Reliable Genetic Tools to Identify, Label, and Target Cardiac Pericytes in Mice

“…Unfortunately, the field of myocardial biology has neglected the pericyte, a cell type of high potential significance in cardiac homeostasis and disease. Associative evidence suggests that pericytes may be involved in early myocardial ischemic injury, 26 may respond to myocardial mechanical stress 25 and neurohumoral stimulation, 9 and may be implicated in fibrosis of the remodeling heart. 65 , 66 Moreover, some studies have suggested that subpopulations of pericytes may have reparative, angiogenic, and even regenerative potential in models of myocardial injury.…”

“…Studies in cells harvested from patients with heart failure have demonstrated that pericytes from cardiomyopathic hearts exhibit impaired mechanotransduction. 25 Moreover, animal model studies have suggested that pericytes may play a role in early postischemic microvascular injury, 26 may be involved in “no‐reflow” following ischemia and reperfusion, 27 , 28 and may contribute to the pathogenesis of the cardiomyopathy associated with receptor tyrosine kinase inhibitor treatment. 29 However, investigations documenting the involvement of pericytes in myocardial diseases using genetic approaches are lacking.…”

Pericyte mechanics and mechanobiology

“…Furthermore, fibronectin induces higher rates of pericyte proliferation and migration (Tigges et al, 2013), an observation that may explain the increased fibronectin levels observed during angiogenesis and development, where pericyte activation and migration are crucial. Interestingly, the mechanoresponse to substrate composition and stiffness is defective in pericytes isolated from end-stage ischemic hearts (Rolle et al, 2020), illustrating the crucial yet poorly understood role of pericyte mechanobiology in diseases.…”

Simple Detection of Unstained Live Senescent Cells with Imaging Flow Cytometry

“…To test our method in a clinically relevant model, we collected samples of cardiac pericytes (CPcs) obtained from patients undergoing cardiac transplantation (E-CPcs) or from healthy donors (D-CPcs). Previous investigation in this model provided preliminary evidence that E-CPcs residing in ischemic failing human hearts are enriched by senescent cells [ 22 , 23 ]. E-CPcs were characterized by reduced proliferation rate (significantly reduced % of Ki-67 positive cells) and increased % of phosphorylated histone H2AX (γH2AX), as well as by increased SA-β-gal-positive cells (measured by microscopy) and activity (measured by Spider-βGAL flow cytometry assay), reminiscent of senescence ( Figure 3 a).…”

“…Importantly, we also applied this method to “ex-vivo” samples of CPc from donors and explanted hearts. It has been previously shown that E-CPc residing in ischemic failing human hearts are senescent and display altered mechano-transduction properties [ 22 , 23 ]. Following a few days in culture, we observed that these cells are similar to senescent cells with the typical morphological changes and an increase in many markers associated with cellular senescence.…”