City Research Online

Abstract

Introduction: The sodium myo-inositol transporter SMIT1 (Slc5a3) and sodium-glucose transporter SGLT2 (Slc5a2) are part of the SLC5 family. Their roles in the vasculature are not well understood. SMIT1 interacts with Kv7 channels to regulate vascular contractility. Meanwhile, SGLT2 inhibitors that lower blood glucose have recently been found to treat heart failure, reduce blood pressure, and relax arteries ex vivo. However, the mechanisms behind SGLT2-inhibitor-induced relaxation and SMIT1’s vascular role remain unclear. This project investigates SGLT1 and SGLT2-inhibitor-induced relaxations and explores SMIT1’s role in regulating arterial tone in male and female vascular beds.

Methods: RT-qPCR, immunocytochemistry, immunohistochemistry, western blot and PLA determined Slc5a protein expression and interactions. Vascular responses were recorded using wire myography and ex vivo morpholino oligonucleotide transfection, determined SMIT1’s role in vascular tone and NHE1’s role in SGLT2-induced relaxations.

Key Results: SMIT1 and SGLT2 proteins were expressed in mesenteric, renal, and coronary arteries of male and female rats, with minimal Slc5a1 and Slc5a11 mRNA transcripts. Hyperosmotic 150 mM raffinose increased SMIT1 membrane expression, reduced vascular contractility, and enhanced vasorelaxation, coinciding with increased interaction of SMIT1 with Kv7.4/5, Gβγ, and SGK1 proteins. Downregulation of SMIT1 increased arterial contractility and reduced relaxant responses to ML213, isoprenaline, and CGRP. SGLT2 inhibitors (1μM-100μM) and cariporide relaxed mesenteric arteries but had little effect on renal and septal arteries. Immunohistochemistry showed dense sensory nerve innervation in mesenteric arteries but not in renal and septal arteries. SGLT2 inhibitor-induced relaxations in mesenteric arteries were reduced by CGRP receptor antagonist BIBN-4096, TRPV1 antagonist AMG-517, and NHE1 knockdown.

Conclusions: This thesis reveals an oestrus cycle difference in SMIT1 expression in vascular smooth muscle cells and a novel role of SMIT1 in regulating vascular contractility through interactions with Kv7.4/5, Gβγ, and SGK. Additionally, SGLT2 inhibitors relax mesenteric arteries by promoting CGRP release from sensory neurons via NHE1 inhibition.

Publication Type:	Thesis (Doctoral)
Additional Information:	The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author.
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology R Medicine > RC Internal medicine
Departments:	School of Health & Medical Sciences > Cardiovascular and Genomics Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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