Intravenous Insulin-like Growth Factor-I Receptor Antisense Treatment Reduces Angiotensin Receptor Expression and Function in Spontaneously Hypertensive Rats

Abstract

The present study investigated the effects of a functional deficit in insulin-like growth factor-I signaling via chronic intravenous administration of insulin-like growth factor-I (IGF-I) receptor antisense in the conscious spontaneously hypertensive rat cardiovascular system. Insulin-like growth factor-I receptor (IGF-IR) antisense, but not full mismatch treatment, decreased IGF-IR expression in both conductance and resistance blood vessels. Aortic IGF-IR density was reduced by 67.4 Ϯ 6.0% in antisense-treated spontaneously hypertensive rat (SHR) compared with untreated animals, whereas mismatch treatment had no effect (analysis of variance, n ϭ 3, P Ͻ 0.01). Aortic and tail artery angiotensin II type 1 receptor expression was significantly reduced by IGF-IR antisense treatment, whereas angiotensin II type 2 receptor expression was unaffected by administration of antisense and mismatch oligonucleotides. IGF-I receptor antisense treatment caused a significant decrease in pressor responses to angiotensin II in comparison with fulllength mismatch treatment (E max was reduced to 65 Ϯ 7 mm Hg compared with 99 Ϯ 6 mm Hg, p Ͻ 0.05). Likewise, a reduction in pressor responses to noradrenaline was observed in hypertensive rats treated with IGF-IR antisense compared with full mismatch-treated rats (E max was reduced to 60 Ϯ 6 mm Hg compared with 108 Ϯ 5 mm Hg, p Ͻ 0.01). There was no clear antisense effect on resting blood pressure and no effect at on aortic medial thickness. These results suggest that although the proliferative and vasodilator effects of IGF-I are impaired in SHR, the effects on angiotensin receptor expression remain profound.A number of differences in the cardiovascular effects of insulin-like growth factor-I (IGF-I) have been identified in hypertensive animal models compared with their normotensive counterparts. Among the many growth-promoting effects of IGF-I is a role as a potent vascular smooth muscle cell mitogen (Du and Delafontaine, 1995), and this proliferative response is blunted in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) (Nolan et al., 2003). An increase in IGF-I mRNA expression, however, is seen in rat models of hypertrophying aorta, portal vein, or urinary bladder (Khorsandi et al., 1992;Chen et al., 1994). IGF-I also causes direct vasodilation via a nitric oxide-dependent pathway Walsh et al., 1996) and relaxes aortic rings precontracted with phenylephrine, an effect also impaired in SHR (Vecchione et al., 2001). Thus, in the vasculature, IGF-I has both pressor-inducing (VSMC mitogenic effect) and depressor effects, and both are altered in hypertensive models, whereas the expression of both the ligand and its receptor may increase in such circumstances.There are profound interactions between IGF-I and the renin-angiotensin system with respect to vascular resistance. In VSMC, angiotensin II has been shown to potentiate IGF-I and IGF-IR expression, and this potentiation has been found to be important in the vascular growth-promoting effects of a...

Effects of Capsaicin and Isoflavone on Blood Pressure and Serum Levels of Insulin-Like Growth Factor-I in Normotensive and Hypertensive Volunteers with Alopecia

“…19) Furthermore, the involvement of IGF-I in regulation of arterial blood pressure is greater in SHR than in WKY. 20) Thus it is possible that activation of sensory neurons leading to an increase in IGF-I x mixed effects model (interaction between group and time) production plays a critical role in the normalization of systolic and diastolic BP in patients with hypertension. Serum levels of IGF-I in the hypertensive patients are significantly lower than those in the normotensive controls.…”

Baroreflex dysfunction in rats submitted to protein restriction

“…Moreover, malnourishment induces direct and/or indirect changes in neurohumoral systems that affect blood pressure regulation (Bell and Slotkin, 1988;Benabe et al, 1993a,b;Benabe and Martinez-Maldonado, 1993;Fernandez-Repollet et al, 1987;Ferreira et al, 2003;Hawkins et al, 2000;Langley-Evans et al, 1996a;Mi et al, 2000). Another important mechanism is related to the production of insulin growth factors (IGF): IGFs are produced under growth hormone (GH) stimulation of the hepatic cells (Conchillo et al, 2007) and are found to be vasodilator via NO production (Begum et al, 1998;Cruzado et al, 2005;Nguyen et al, 2006;Vickers et al, 2001). In malnourished animals, the production of GH may be impaired because of high levels of corticosterone (Langley-Evans et al, 1996a).…”

Involvement of insulin-like growth factor 1 receptor transactivation in endothelin-1-induced signaling in vascular smooth muscle cells

“…Moreover, the studies showing that dominant negative or antisense oligonucleotides (ASO) of IGF-1R are able to attenuate neointima formation in an injured carotid artery rat model (Lim et al 2004) and reduce Ang II type 1 receptor (AT 1 R) expression and function in spontaneously hypertensive rats (Nguyen et al 2006) supports a potential pathogenic role of up-regulated IGF-1R signalling in vascular disease.…”