ORCID Profile
0000-0001-5477-2047
Current Organisation
University of Melbourne
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Publisher: American Physiological Society
Date: 11-2016
DOI: 10.1152/AJPHEART.00316.2016
Abstract: We investigated the acute effects of glucagon-like peptide-1 (GLP-1), GLP-1(1–36), and GLP-1(7–36) on vascular endothelial growth factor-A (VEGFA)-induced endothelium-dependent signaling and vasodilation. Our hypothesis was that GLP-1 released from intestinal l-cells modulates processes related to PLCγ activation, Src, and endothelial NOS (eNOS) signaling, thereby controlling endothelial vessel tone. By using RT-PCR analysis, we found mRNA for the GLP-1 receptor (GLP-1R) in human dermal microvascular endothelial cells (HDMEC), human retinal microvascular endothelial cells, and rat arteries. In isolated rat mesenteric resistance arteries precontracted with the thromboxane analog U46619 to 80–90% of maximum contraction, VEGFA (25 ng/ml) caused a small and gradual relaxation (28.9 ± 3.9%). Pretreatment of arteries with either GLP-1(1–36) (500 nM) or GLP-1(7–36) (1 nM) abolished the VEGFA-induced relaxation. VEGFA-induced relaxations were also inhibited in endothelial-denuded arteries and in arteries pretreated with the nitric oxide synthase (NOS) inhibitor, Nω-nitro-l-arginine methyl ester (100 μM). In vivo studies on male Wistar rats also revealed that GLP-1(7–36) inhibited VEGFA-induced vasodilation of the same arteries. In isolated endothelial cells, GLP-1(1–36) and GLP-1(7–36) caused a reduction in VEGFA-induced phosphorylation of PLCγ. Ca 2+ imaging of endothelial cells and rat mesenteric resistance arteries using fura-2, revealed that both GLP-1 analogs caused a reduction in VEGFA-induced Ca 2+ signaling. GLP-1(1–36) also reduced VEGFA-induced eNOS phosphorylation in HDMEC. In conclusion, GLP-1 reduced relaxation induced by VEGFA in resistance arteries by inhibiting VEGFR2-mediated Ca 2+ signaling and endothelial NO synthesis. GLP-1, on its own, also induced phosphorylation of Src and ERK1/2 that can lead to proliferation and is implicated in vessel permeability.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2018
DOI: 10.1161/HYPERTENSIONAHA.117.10152
Abstract: Microtubules can regulate GPCR (G protein–coupled receptor) signaling in various cell types. In vascular smooth muscle, activation of the β-adrenoceptor leads to production of cAMP to mediate a vasorelaxation. Little is known about the role of microtubules in smooth muscle, and given the importance of this pathway in vascular smooth muscle cells, we investigated the role of microtubule stability on β-adrenoceptor signaling in rat renal and mesenteric arteries. In isometric tension experiments, incubation with the microtubule inhibitors colchicine and nocodazole enhanced isoprenaline-mediated relaxations of renal and mesenteric arteries that the microtubule stabilizer, paclitaxel, prevented. Sharp microelectrode experiments showed that colchicine treatment caused increased hyperpolarization of mesenteric artery segments in response to isoprenaline. Application of the Kv7 channel blocker, XE991, attenuated the effect of colchicine on isoprenaline relaxations, whereas iberiotoxin—a BKCa channel blocker—had no effect. In addition, colchicine improved the relaxations to the Kv7.2 to 7.5 activator, S-1, in both renal and mesenteric artery segments compared with dimethyl sulfoxide incubation. We determined that increased mesenteric artery myocytes treated with colchicine showed increased Kv7.4 membrane expression, but Western blot analysis showed no change in total Kv7.4 protein. This study is the first to show microtubule disruption improves the β-adrenoceptor–mediated relaxations of mesenteric and renal arteries and determine this enhancement to be because of increased membrane expression of the Kv7 voltage-gated potassium channels.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Wiley
Date: 05-01-2018
DOI: 10.1111/BPH.14097
Publisher: Wiley
Date: 26-04-2019
DOI: 10.1111/APHA.13279
Abstract: This study aimed to assess intracellular Ca Ca Schwann cells but not axons responded with a Ca Modification of [Ca
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 15-10-2017
DOI: 10.1111/BPH.14034
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.EJPHAR.2016.01.004
Abstract: In rabbits with cellophane renal wrap hypertension, hindquarter and total vascular resistance changes to pressor and depressor agents are lified compared to those of normotensive rabbits. The aim of the present study was to evaluate the in vitro pharmacodynamics of hypertensive and normotensive rabbit small artery segments isolated from the renal and hindquarter vascular beds. Using wire myography, the full range (Emax) and sensitivity (EC50) to a range of agonists of segments of renal interlobar (≈ 600 µm i.d.), renal arcuate (≈ 250 µm i.d.) and deep femoral branch (≈ 250 µm i.d.) arteries were assessed under normalised conditions of passive tension. Interlobar arteries from hypertensive rabbits were more sensitive (EC50) than those from normotensive rabbits to noradrenaline (6-fold), methoxamine (3-fold) and angiotensin II (3-fold). Arcuate artery reactivity was largely unaffected by hypertension. Deep femoral arteries from hypertensive rabbits had enhanced sensitivity only to noradrenaline (2-fold) and methoxamine (4-fold). Sensitivity to relaxation by acetylcholine was unaffected by hypertension in all arteries. Deep femoral arteries from hypertensive rabbits were more sensitive to sodium nitroprusside than normotensive counterparts. Adenosine caused little relaxation in renal arteries, but full relaxation in deep femoral arteries, unaltered by hypertension. This study found substantial heterogeneity in the pharmacodynamic profile of vessels isolated from different vascular beds and between arterial segments within the kidney. These profiles were differentially affected by hypertension suggesting that hypertension per se is not a resultant of general vascular dysfunction.
No related grants have been discovered for Makhala Khammy.