The Vasoactive Potential of Kisspeptin-10 in the Peripheral Vasculature

Abstract

Splice products of the Kiss1 protein (kisspeptins) have been shown to be involved in a diverse range of functions, including puberty, metastasis and vasoconstriction in large human arteries. Circulating Kisspeptin-10 (Kp-10) plasma levels are low in normal individuals but are elevated during various disease states as well as pregnancy. Here, we investigated the potential of Kp-10, the shortest biologically active kisspeptin, to influence microvascular effects, concentrating on the cutaneous vasculature. Kp-10 caused a dose-dependent increase in oedema formation (0.3–10nmol/injection site), assessed by Evans Blue albumin dye extravasation, in the dorsal skin of CD1 mice. Oedema formation was shown to be inhibited by the histamine H1 receptor antagonist mepyramine. The response was characterised by a ring of pallor at the injection site in keeping with vasoconstrictor activity. Therefore, changes in dorsal skin blood flow were assessed by clearance of intradermally injected 99mtechnetium. Kp-10 was found to significantly reduce clearance, in keeping with decreased blood flow and providing further evidence for vasoconstrictor activity. The decreased clearance was partially inhibited by co-treatment with the cyclo-oxygenase inhibitor indomethacin. Finally evidence for the kisspeptin receptor gene (Kiss1R), but not the kisspeptin peptide gene (Kiss1), mRNA expression was observed in heart, aorta and kidney samples from normal and angiotensin II induced hypertensive mice, with similar mRNA levels observed in each. We have evidence for two peripheral vasoactive roles for kisspeptin-10. Firstly, plasma extravasation indicative of ability to induce oedema formation and secondly decreased peripheral blood flow, indicating microvascular constriction. Thus Kp-10 has vasoactive properties in the peripheral microvasculature.

Kisspeptin-10 induces endothelial cellular senescence and impaired endothelial cell growth

“…Both KP and its receptor GPR54 were detected in HUVECs (Figure 2A). The previous [15,20] and present studies suggest that endothelial cells may serve as an alternative source of KP and, thereby, act in a local paracrine/autocrine fashion. The levels of KISS1 mRNA transcripts were significantly enhanced in the HUVECs cultured under the mimicked ischaemic conditions compared with those cultured under the normal conditions ( Figure 2B; P < 0.05).…”

Inotropic Action of the Puberty Hormone Kisspeptin in Rat, Mouse and Human: Cardiovascular Distribution and Characteristics of the Kisspeptin Receptor

“…However, to date mRNA studies of kisspeptin receptor distribution in whole heart samples have reported low but varying mRNA expression by northern blot [2], expression was not detected by PCR [3], [4], [32] except by Sawyer and colleagues, who were also able to detect mRNA encoding murine kisspeptin, albeit at very low copy number [46]. We now report for the first time, the expression of kisspeptin and the kisspeptin receptor protein in human, rat and mouse heart, and have shown that kisspeptins are potent positive inotropes in in vitro cardiac preparations from these species.…”

Potent Vasoconstrictor Kisspeptin‐10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist

“…Mice at 13 weeks of age were infused for 4 weeks with KP‐10 and/or P234, a GPR54 antagonist (Peptide Institute, Osaka, Japan), using osmotic minipumps (Model 1002; Alzet; DURECT Corporation, Cupertino, CA). The time course and dose of KP‐10 and P234 infusion were decided on the basis of others’ previous and our preliminary data …”