RT info:eu-repo/semantics/doctoralThesis
T1 Kv1.3 channels and vascular smooth muscle phenotypic modulation: A new therapeutical target for vascular diseases
A1 Moreno Estar, Sara
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Enfermedades vasculares
K1 Vascular remodeling Kv1.3
K1 Remodelado vascular Kv1.3
K1 2411.03 Fisiología Cardiovascular
AB Differentiated vascular smooth muscle cells (VSMCs) from the vessel wall exhibit contractile phenotype that allows them to participate in the regulation of vessel lumen diameter. In response to vascular wall injury, these cells are able to change their phenotype, in a process known as phenotypic modulation (PM). This physiological process allows cells to proliferate and migrate into the damaged tissue for renewal. However, excessive PM can have harmful consequences that determine the development of various pathologies associated with cardiovascular disease. In this work, we will focus on two main pathologies resulting from PM processes: intimal hyperplasia (IH) and vascular calcification (VC). IH is the pathophysiological process that explains the failure of bypass surgeries and angioplasty with or without stenting, since surgery initiates excessive remodeling that reoccludes the vessel. Previous work by our group demonstrated that increased functional expression of the Kv1.3 channel contributes to PM of VSMCs, since Kv1.3 blockers inhibit migration and proliferation. In addition, Kv1.3 blockade also inhibits IH in human vessel rings in organ culture and in an in vivo mouse model of vascular injury. In this work, we have further investigated the role of Kv1.3 channels in the PM of VSMCs. We explored in one hand the possibility of using blockers of these channels (alone or in combination) as new anti-restenosis therapies. In addition, we analyzed the contribution of the Kv1.3 channel to PM in response to VSMCs dedifferentiation towards an osteogenic phenotype leading to VC.We found that local, perivascular application of a PAP-1- (a Kv1.3 blocker) releasing hydrogel effectively and safely decreases the development of IH. We conclude that PAP-1 could represent a new anti-restenotic therapy in drug-eluting stents. However, when we explored the combined use of the Kv1.3 blocker (which acts through the MAPK pathway) together with everolimus (an mTOR pathway inhibitor, the current treatment in stents) we found that, although the drugs inhibit IH when administered separately, their effects are nullified in combination. These results were replicated in vivo, ex vivo and in vitro, and led us to explore the molecular targets of this suppressive effect. We found that P70S6K activation replicated our functional experiments, and that it is the migratory (and not the proliferative) response of VSMCs in vitro what correlates with remodeling in vivo. Finally, we have explored the contribution of Kv1.3 in the development of CV associated with chronic kidney disease (CKD). Our previous studies indicated that Kv1.3 channel blockers were able to reverse the calcification of VSMCs induced by uremic serum from CKD patients in in vitro models. In this work, we have developed in vivo and ex vivo models of CKD to explore the role of Kv1.3 blockers in the development of arterial stiffness that characterizes CV. We observed increased vascular stiffness in our model of CKD that was reproduced in organ culture of vessels with uremic serum. Furthermore, our results demonstrate that Kv1.3 blockade prevents this remodeling but cannot reverse it once it is initiated.We conclude that Kv1.3 channel is relevant for the regulation of PM in its early stages, so that its blockade represents a useful tool in the prevention of vascular diseases associated with VSMCs PM.
YR 2023
FD 2023
LK https://uvadoc.uva.es/handle/10324/69575
UL https://uvadoc.uva.es/handle/10324/69575
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 15-oct-2024