Les cellules endothéliales peuvent acquérir un phénotype mésenchymateux associé avec l’expression de la protéine nestine dans un modèle d’hypertrophie cardiaque et de fibrose réactive

Cardiac hypertrophy secondary to an ischemic insult or a hemodynamic overload represents the primary response of the heart to enhance compromised cardiac function. However, a pathological consequence of cardiac hypertrophy is reactive fibrosis characterized by the uncontrolled synthesis and deposition of collagen by proliferating myofibroblasts. Furthermore, the unrestrained accumulation of collagen in the hypertrophic heart leads to increased cardiac stiffness and progressive worsening of contractile function. Previous studies have reported that the intermediate filament protein nestin was re-expressed in myofibroblasts during reparative fibrosis and played a direct role in cell proliferation. Based on these observations, the following study tested the hypothesis that nestin was induced in myofibroblasts secondary to the development of reactive fibrosis in the heart of rats subjected to suprarenal aortic constriction. Two weeks following suprarenal aortic constriction of the adult male rat, a concentric pattern of cardiac hypertrophy was observed and associated with an overt reactive fibrotic response characterized by the increased deposition of collagen in the interstitium and perivascular region of numerous blood vessels. Nestin protein levels were significantly increased in the heart of hypertrophied rats and expression positively correlated with mean arterial pressure and left ventricular systolic pressure. Immunofluorescence approach revealed an increased appearance of nestin-immunoreactive cells in the interstitium and perivascular region of hypertrophied hearts and exhibited a mesenchymal phenotype characterized by collagen co-staining. The latter data suggests that resident fibroblasts may have expressed nestin and/or was induced in response to pro-fibrotic factors implicated in reactive fibrosis. Indeed, the exposure of normal myofibroblasts and myofibroblasts isolated from the hypertrophied heart to AII, TGF-B1 and EGF significantly increased nestin protein levels, whereas α-SMA expression remained unchanged. Moreover and predominantly in the hypertrophied heart, displaced non-vascular CD31(+) cells were detected in the interstitium and perivascular region that co-expressed nestin and collagen suggesting a transition of endothelial cells to a mesenchymal phenotype. Indeed, filamentous nestin was detected in human coronary artery endothelial cells and exposure to TGF-B1 induced collagen expression. By contrast, collagen was detected in CD31(+) rat microvascular endothelial cells whereas nestin expression was absent. In response to TGF-B1 and EGF, nestin was expressed in rat microvascular endothelial cells but the reported filamentous phenotype was not observed.  Collectively, these data support the premise that the progression of the reactive fibrotic response in the hypertrophied heart secondary to suprarenal aortic constriction was attributed in part to the increased appearance of nestin(+) mesenchymal cells originating in part from resident ventricular myofibroblasts. Moreover, the in vivo and in vitro data further suggest that displaced endothelial cells may represent an additional source of nestin(+) mesenchymal cells in the hypertrophied heart contributing to the development of reactive fibrosis. Targeting nestin may represent a potential therapeutic approach to attenuate the reactive fibrotic response regardless the cellular origin of the mesenchymal cell.

Keyphrases: Hypertension artérielle, Nestin, Cardiac hypertrophy, Reactive fibrosis, Mesenchymal cells, Endothelial cells