Implication des cellules Nestin+ dans le remodelage vasculaire en conditions pathologiques

The intermediate filament protein Nestin, previously identified as a neural stem cell marker, is expressed in vascular cells. It has been shown that aortic cells expressing Nestin originate from the neural crest. Endothelial Nestin+ cells are found in capillaries during embryogenesis and in during tumour vascularization. Nestin expression is a characteristic feature of the proliferative endothelium. However, Nestin+ expression was also detected in smooth muscle cells in the vascular wall of the rat aorta. The regulation of Nestin expression in physiological development and pathological situations remain unknown. The focus of the following studies consists of analyzing Nestin expression in the carotid and aorta during vascular remodeling secondary to type I diabetes or hypertension. The present study tested the hypothesis that Nestin expression plays a role in vascular homeostasis during the physiological postnatal development and in vascular pathologies. Nestin protein levels were strongly expressed in the neonatal rat aorta and its expression was reduced with physiological development. Nestin expression was found in endothelial cells and in a subpopulation of vascular smooth muscle cells. Nestin protein expression in vascular smooth muscle cells in the aorta correlated with the proximity of the vessel to the heart, with levels of expression greater in the aortic arch versus the thoracic region. We have determined that the intermediate filament protein was downregulated in an experimental model of type I diabetes. This loss of Nestin expression was an early event in diabetic pathology preceding endothelial dysfunction. The decreased expression of Nestin was associated with the reduced entry of vascular smooth muscle cells into the cell cycle. The density of vascular smooth muscle cells expressing phosphorylated phosphohistone 3 in type I diabetic rats was significantly decreased and correlated with the loss of Nestin expression. In vitro experiments recapitulated the in vivo findings as the exposure of VSMCs to hyperglycaemia reduced Nestin expression and concomitantly inhibited VSMCs proliferation. The proliferative role of Nestin was confirmed as shRNA-mediated depletion of the intermediate filament protein decreased basal proliferation of vascular smooth muscle cells, as reflected by a reduced uptake of [3H] thymidine.  In a rat model of pressure-overload, the accompanying hypertensive response was associated with the increased Nestin expression in the carotid artery. A positive correlation was observed between Nestin expression in the carotid artery and mean arterial pressure. Furthermore, peptide growth factors implicated in vascular remodelling secondary to hypertension increased Nestin expression in vascular smooth muscle cells. Lastly, the depletion of Nestin expression via a shRNA attenuated peptide growth factor stimulated the uptake of [3H] thymidine, associated with cell proliferation,.whereas the uptake of [3H] leucine, associated with the protein synthesis was unaffected. These data suggest that Nestin upregulation in the vasculature secondary to hypertension may represent an adaptive response to promote vascular smooth muscle cell growth to accommodate the increase in blood pressure.

Keyphrases: Hypertension, Nestin, Smooth muscle cells, Endothelial cells, Diabetes, Hypertension, Vascular remodelling, Angiogenesis