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(Hypertension. 1997;29:691-699.)
© 1997 American Heart Association, Inc.

Articles

Insulin and Insulin-Like Growth Factor in Normal and Pathological Cardiovascular Physiology

James R. Sowers, Principal Discussant

the Divisions of Endocrinology, Metabolism, and Hypertension, Wayne State University School of Medicine and VA Medical Center, Detroit, Mich.

Correspondence to James R. Sowers, MD, Director, Division of Endocrinology, Metabolism, and Hypertension, Wayne State University School of Medicine, 4201 St Antoine, UHC-4H, Detroit, MI 48201. E-mail sowers@oncgate.roc.wayne.edu

Key Words: insulin • insulin-like growth factor • endothelium • nitric oxide • vasculature

	Introduction

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
Over the past decade considerable data have been garnered suggesting that insulin, normally secreted only by the pancreas, and IGF-1, secreted by cells of the cardiovascular system, regulate normal cardiovascular physiological responses.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 101 102} Furthermore, there is emerging evidence that abnormal actions of these factors may contribute to disease states such as hypertension and atherosclerosis.^{38 39} This review presents the current understanding of mechanisms of the hemodynamic, metabolic, and growth effects of insulin and IGF-1 exerted on cardiovascular tissue under both normal and pathological conditions.

	Hemodynamic Actions of Insulin and IGF-1

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
Insulin and IGF-1 have specific and physiological vascular actions in humans and experimentally derived animals and cause an increase in SMBF and a decrease in vascular resistance.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41} Studies by several investigative groups^{29 30 31 32 33 34 35 40} have shown that insulin increases SMBF in a dose-dependent fashion, with an ED₅₀ for insulin of approximately 35 to 40 µU/mL in lean insulin-sensitive persons.⁴⁰ In experimental animals, insulin has differential effects in different vascular beds, exerting vasodilatory effects on the femoral, aortic, coronary, and tail vasculature and vasoconstrictor effects in mesenteric arteries.^{2 3 14 15 16 99 100 101 102} There are also differential effects of insulin in the renal vascular bed, exerting a constricting effect on afferent arterioles and efferent arteriole vasodilation.¹⁰¹ Even gender differences in vascular responses to insulin have been reported.¹⁰² IGF-1 has effects on the regulation of vascular tone that are similar to those of insulin, with regional differences in vascular responses.^{31 36 38 39 103 104 105} Unlike insulin, however, IGF-1 is produced in cardiovascular tissue,^{8 9 10 11 12 38 39 40 41} where it likely exerts autocrine/paracrine effects.

	Role of NO in the Vascular Effects of Insulin and IGF-1

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
The endothelium-derived relaxing factor NO appears to be an important mediator of insulin-induced and IGF-1–induced vascular relaxation.^{13 14 29 30 31 38 39 40 41} Using a specific inhibitor of NOS, L-NMMA, investigators^{29 30 106} have demonstrated that insulin-mediated and IGF-1–mediated increases in SMBF are dependent on vascular NO production. Similar studies in experimental animals have demonstrated that both insulin-mediated and IGF-1–mediated vasorelaxation are NO dependent.^{31 38 39 40 41} Indeed, studies conducted in my laboratory (Fig 1) and others^{13 14} indicate that these hormones stimulate NO production in cultured vascular endothelial cells. Although it has been suggested that the vasorelaxant effects of insulin-related factors are mediated through endothelium-derived NO production, the relatively slow (30 to 60 minutes) effects of insulin/IGF-1 on vascular tone^{29 30 36 39 40 106} suggest that other mechanisms may be involved.

View larger version (39K): [in this window] [in a new window]   Figure 1. Effects of estradiol (bE2) and IGF-1 on endothelial cell NO production under normal (5 mmol/L) and high (20 mmol/L) glucose concentration.

Our laboratory recently reported that rat tail artery contractile responses to both KCl and norepinephrine in vitro were significantly attenuated by IGF-1 administered systematically in vivo 90 minutes before removing the tail arteries (Fig 2).^{39 105} Similar data were obtained when rat tail artery rings were preincubated in vitro for 90 minutes, and L-NAME, an inhibitor of NO production, administered either in vivo or in vitro, reversed the IGF-1 attenuation of vascular contractility (Fig 3).³⁹ We also observed in rat tail vascular strips a significant increase in IGF-1 stimulation of NO production over the same 90-minute period (Fig 4).³⁹ This and preliminary data from our laboratory indicating that insulin and IGF-1 stimulate both rapid (presumably constitutively regulated NO production/cNOS) and more delayed NO production (iNOS) in cultured VSMCs suggest that these hormones stimulate VSMC and endothelial cell production of NO (Fig 5). One investigative team reported that insulin acutely increases intact endothelial cell [Ca²⁺]_i and relaxes VSMCs in an L-NMMA–dependent manner.²⁷ Insulin-mediated and IGF-1–mediated inhibition of VSMC contraction likely occurs via stimulation of the synthesis of NO in both endothelial cells and VSMCs, which in turn increases the VSMC production of cGMP.^{37 38 39} Alternatively, the increased NO could reduce VSMC [Ca²⁺]_i^{5 6 7 38 107} by stimulating the Na⁺,K⁺-ATPase pump^{108 109} or by directly activating Ca²⁺-dependent K⁺ channels¹¹⁰ in VSMCs, which indirectly causes decreased Ca²⁺ influx via voltage-operated channels (Fig 6).^{37 41 110}

View larger version (25K): [in this window] [in a new window]   Figure 2. A, In vitro contractility 90 minutes after in vivo IGF-1. Responses to both KCl (top) and norepinephrine (bottom) were attenuated. B, Dose responses to KCl (top) and norepinephrine (bottom) 90 minutes after in vitro preincubation with 100 nmol/L IGF-1.39 *indicates P<.001.

View larger version (15K): [in this window] [in a new window]   Figure 3. Coincubation with L-NAME (100 µmol/L) and IGF-1 (100 nmol/L) for 90 minutes reversed the IGF-1 induced inhibition for both KCl and for norepinephrine.39

View larger version (29K): [in this window] [in a new window]   Figure 4. Nitrite/nitrate accumulation as an index of NO production in control and IGF-1–exposed aortas after 90 minutes of incubation.39 *indicates P<.05.

View larger version (30K): [in this window] [in a new window]   Figure 5. Effects of insulin and IGF-1 on VSMC [Ca2+]i and [Mg2+]i and associated VSMC contractility as mediated through modulation of both endothelial and VSMC NO production. AII indicates Ang II.

View larger version (28K): [in this window] [in a new window]   Figure 6. Mechanisms regulating divalent cation metabolism and contraction in vascular smooth muscle cells and proposed targets of insulin and IGF-1 action. Pivotal steps in regulation of divalent cation metabolism are indicated by circled numbers.1 IP3 indicates inositol tris-phosphate; DAG, diacylglycerol.

	Effects of Insulin and IGF-1 on VSMC Cation Metabolism

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
One mechanism by which insulin and IGF-1 attenuate vascular contractility is through effects on VSMC divalent cation metabolism (Fig 6).^{1 5 6 7 16 24 25 26 27 37 38 39 68 69 107 108 109 110} These hormones reduce Ca²⁺ influx into VSMCs by attenuating both voltage- and receptor-operated Ca²⁺ channels in conjunction with reductions in VSMC contractile responses, as measured by VSMC video-imaging techniques.^{5 6 7 15 26 27} Another mechanism by which insulin and IGF-1 may modulate VSMC [Ca²⁺]_i, and thus vascular contractility, is through stimulation of the Na⁺,K⁺-ATPase pump, which would reduce [Ca²⁺]_i via changes in Na⁺-Ca²⁺ exchange.¹¹¹ Insulin and IGF-1 stimulate Na⁺,K⁺-ATPase activity (primarily its catalytic ouabain-sensitive -subunits) in various tissues, including VSMCs (Fig 7).^{38 108} There is evidence that this stimulation occurs by increases in message expression of new catalytic pump subunits,¹⁰⁸ secondary to mass action effects of Na⁺ (via activation of Na⁺-H⁺ exchange),^{38 112} by modification of the enzyme's affinity for ATP, Na⁺, and K⁺,¹¹³ or by increasing translocation of preformed Na⁺,K⁺-ATPase molecules to the plasma membrane.^{38 114 115} Recently observed effects of insulin and IGF-1 to increase VSMC glucose transport^{38 41 116} may also contribute to regulation of the pump. Since VSMC Na⁺,K⁺-ATPase stimulates the transport of Na⁺ and K⁺ ions against concentration gradients, energy must be supplied in the form of ATP hydrolysis.¹¹⁷ Thus, the Na⁺,K⁺-ATPase pump is a major consumer of ATP in VSMCs.^{117 118} ATP generated by aerobic glycolysis is preferentially used for this process,^{117 118} suggesting that insulin/IGF-1–mediated glucose transport, and thus intracellular availability of glucose, is a potentially important mechanism by which hormones stimulate pump activity in VSMCs (Fig 6).

View larger version (22K): [in this window] [in a new window]   Figure 7. Effects of IGF-1 antibody (anti–IGF-1) stretch-induced increases in DNA synthesis rate. In association with cyclic stretch, we have observed increases in VSMC IGF-1 and NO in conjunction with thymidine incorporation.41

NO produced by endothelial cells and VSMCs also regulates the Na⁺ pump.¹⁰⁹ Incubation of endothelium-denuded aorta with NO or an NO donor, nitroprusside, caused a time-dependent increase in ouabain-sensitive ⁸⁶Rb uptake, perhaps by stimulating Na⁺-H⁺ exchange.¹⁰⁹ This NO-mediated stimulator of the pump could, in part, explain the NO-induced hyperpolarization of VSMCs.¹¹⁹ Studies by several groups^{109 120 121} suggest that insulin-mediated NO stimulation of the pump is mediated through activation of soluble guanylate cyclase and increases in cGMP. Insulin acutely increases cGMP production by cultured human VSMCs¹²⁰ and reduces contraction of isolated VSMCs,^{7 15} a phenomenon blocked by L-NMMA.¹²¹ Furthermore, in rat cardiomyocytes, insulin potentates cytokine-induced NO release by increasing L-arginine uptake.¹²² Unpublished data from our laboratory indicate that both cNOS and nNOS are present in VSMCs and that there are both rapid and delayed releases of NO induced by insulin/IGF. The slower production of NO occurs over hours and is inhibited by dexamethasone, cycloheximide, and aminoguanidine, suggesting transcription and translation of iNOS (Fig 5). Insulin/IGF-1 may also stimulate the Na⁺,K⁺-ATPase pump by increasing VSMC [Mg²⁺]_i, a process that appears defective in states of insulin resistance/deficiency.³⁸

	Activation of the Sympathetic Nervous System by Insulin/IGF-1

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
In addition to its vasodilatory effects, acute hyperinsulinemia induces systemic sympathetic activation measured by direct muscle sympathetic nerve activity measurements.^{4 123 124} This sympathetic nervous system activation is due to hyperinsulinemia per se and not to associated glucose infusion in clamp procedures.¹²⁴ However, there are data suggesting that acute hyperinsulinemia-induced sympathetic activation is due to a baroreflex-mediated response to a slight insulin-induced vasodilation. This notion, which couples sympathetic activation and vasodilation, is supported by the observation that in autonomous failure, insulin causes hypotension.¹²⁵ Nevertheless, there is evidence that insulin may chronically stimulate the SNS through central nervous system actions, as extensively reviewed.⁴²

	Actions of Insulin/IGF-1 Regulation of Carbohydrate Metabolism in Cardiovascular Tissue

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
Insulin/IGF-1 regulates glucose transport in cardiovascular tissue^{1 38 126 127 128} and in classical insulin-sensitive tissue, such as skeletal muscle and fat.¹²⁶ Facilitative glucose transport depends on the functionality of a family of transmembrane proteins, which include GLUT-1 and GLUT-4, which are expressed in mammalian heart^{82 126} VSMCs.^{38 41 126 127 128 129} GLUT-1 is present on the cell membrane and is therefore responsible for basal glucose uptake, and GLUT-4 is associated with intracellular membranes, is mobilized by insulin/IGF-1 to the cell surface, and is responsible for the increases in glucose uptake under insulin/IGF-1 stimulation.¹²⁶ Insulin stimulates GLUT-4 translocation to rat myocardial sarcolemma^{129 130} and glucose transport.¹³¹ Hearts from diabetic animals have a decreased rate of glucose uptake¹³² and decreases in GLUT-1 and GLUT-4 expression and levels.^{133 134} Furthermore, insulin treatment in insulinopenic diabetic rats normalizes glucose uptake as well as a return to tissue GLUT-4 expression and protein levels.¹³⁴ These observations underscore the importance of insulin in regulating myocardial carbohydrate metabolism.

IGF-1 and insulin increase glucose uptake in cultured VSMCs.^{38 116} This increase in glucose transport occurs via a protein synthesis–independent pathway. As GLUT-4 is expressed in VSMCs,³⁸ this stimulation appears to be accomplished by translocation of this insulin/IGF-1–sensitive glucose transporter.³⁸ The maximal velocity for glucose transport is altered in VSMCs from insulin-resistant Zucker obese rats.¹¹⁶ This observation is relevant to actions of insulin/IGF in regulating vascular tone, because glucose transport in VSMCs appears to be critical for regulation of vascular contractility¹¹⁸ and cation transport.¹¹⁷ Thus, decreased IGF-1/insulin–mediated glucose in VSMCs could contribute to the decreased ability of IGF-1/insulin to stimulate vascular NO production¹⁴ and the Na⁺,K⁺-ATPase pump^{38 108 109} and to attenuate VSMC [Ca²⁺]_i and contractile responses to vasoconstrictors.^{16 38 116}

	Role of Insulin Resistance and/or Hyperinsulinemia in Pathogenesis of Hypertension

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
Investigations have shown an association between insulin resistance, hyperinsulinemia, and hypertension.^{42 43 44 45 46 47 48 49 50 51 52 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69} One notion that has developed is that the diminished response to insulin's action on glucose uptake in skeletal muscle and fat (classical sites of insulin action) leads to compensatory hyperinsulinemia, which, in turn, elicits responses of the kidneys, SNS, and the cardiovascular system.^{85 86 87 88 89 90 91 92 93 94 95} This notion presupposes that insulin resistance is selective to specific tissues (ie, skeletal muscle and fat), whereas other tissues, such as the kidneys and SNS, retain their sensitivity to insulin.^{42 94} However, there is evidence that insulin, per se, does not contribute to the pathogenesis of hypertension.⁹⁴ Acutely, insulin is a vasodilator in most vascular beds,^{1 2 3 4 16 17 18 19 28 29 30 31 32 33 34 35 36 37 38 39 40} and long-term insulin infusion in dogs reduces pressor responses and lowers blood pressure.^{94 95} Furthermore, blood pressure is generally not elevated in persons with insulinomas, and some epidemiological studies have failed to confirm a relationship between plasma insulin concentrations and hypertension,^{94 135 136} particularly in Pima Indians and Mexican-Americans.^{135 136} Thus, accumulative data indicate that insulin resistance and hyperinsulinemia alone are not sufficient to cause hypertension. However, this does not negate the notion that insulin resistance, under some circumstances, contributes to the pathogenesis of hypertension similar to other pathophysiological factors, such as salt, the SNS, and the renin-angiotensin system.

Investigators have proposed the hypothesis that abnormalities in skeletal muscle vascular and sympathetic regulation/interaction underlie insulin resistance in essential hypertension and obesity.^{32 40 42 61 65 66 67 84 137} Accordingly, primary abnormalities could relate to hyperinsulinemia, activating the SNS, or to exaggerated activations of the SNS, causing insulin resistance. Several investigators^{32 61 65 92 138} have conducted studies suggesting that insulin evokes an exaggerated muscle sympathetic response in essential hypertension, obesity, and type II diabetes, which is mediated by mechanisms involving the central nervous system. However, in carefully conducted studies, hyperinsulinemic type II diabetic patients displayed normal SNS responses to lower body negative pressure.¹³⁹ Furthermore, insulin resistant/hyperinsulinemic obese persons have been reported to be normally responsive to sympathetic stimuli.¹⁴⁰ In the studies conducted by Tack et al,¹³⁹ SNS responses to hyperinsulinemia were not impaired. Thus, the role of SNS/hyperinsulinemia interactions in the pathogenesis of hypertension in these hyperinsulinemic conditions remains unresolved.

There is also evidence that insulin and Ang II may interact to have hypertensinogenic actions. For example, euglycemic hyperinsulinemia has been reported to have a dose-related effect, ie, an increase in the blood pressure rise caused by Ang I infusion; insulin has been reported to increase mesangial cell responsiveness to Ang II¹⁴¹ ; and hyperinsulinemic/insulin-resistant Zucker obese rats have increased blood pressure sensitivity to Ang II.⁹⁰ Recent studies conducted by Brands et al¹⁴² showed that ACE inhibition prevented the hypertension from developing insulin-induced hypertension, suggesting that a functional renin-angiotensin system is necessary for complete expression of insulin-induced hypertension in rats. The relevance of these observations in humans needs further exploration because many insulin-resistant hyperinsulinemic persons have low levels of plasma renin activity.¹

There is also considerable evidence that altered cardiovascular divalent cation metabolism may explain the relationship between insulin resistance and hypertension. Increased vascular resistance and vasoconstrictor responses to agonists occur in both insulinopenic and insulin-resistant conditions.¹ In both of these conditions there are abnormalities in cardiovascular [Ca²⁺ ]_i metabolism.¹⁴³ For example, agonist-induced VSMC [Ca²⁺]_i and vascular reactivity responses are exaggerated in the hyperinsulinemic/insulin-resistant Zucker rat.^{16 90} Increased VSMC [Ca²⁺]_i may be related, in part, to diminished activity of the membrane Na⁺,K⁺-ATPase pump (Fig 6).^{37 38} Decreased activity of this pump has been observed in both insulin-resistant^{144 145} and insulin-deficient states^{143 146} in tissues in which glucose is modulated by insulin (ie, skeletal, cardiac, and vascular smooth muscle tissue). An isoform-specific reduction in the expression of the aortic ₂ catalytic subunit of the pump,¹⁴⁷ in conjunction with increased [Ca²⁺]_i¹⁴⁸ and vascular tone, has been observed in insulin-resistant spontaneously hypertensive rats.¹⁴⁹ Elevated [Ca²⁺]_i is associated with attenuated insulin-stimulated glucose transport in several insulin-sensitive tissues.¹⁵⁰ Thus, altered VSMC [Ca²⁺]_i regulatory mechanisms may represent a fundamental abnormality associated with both impaired VSMC insulin and IGF-1 action, increased VSMC [Ca²⁺]_i, and enhanced vascular resistance.^{37 38 41 68}

Increased peripheral vascular resistance characteristic of hypertension associated with insulin resistance may also be related to abnormalities of intracellular [Mg²⁺]_i metabolism.^{1 38 151} Insulin increases cellular uptake of Mg²⁺,¹⁵¹ and in conditions of decreased cellular insulin action (ie, type I and type II diabetes), there is a reduction in [Mg²⁺]_i.^{151 152} Depletion of tissue [Mg²⁺]_i contributes to decreased insulin-stimulated glucose uptake.¹⁵² Although the mechanism by which [Mg²⁺]_i depletion leads to insulin resistance is unclear, decreases in [Mg²⁺]_i may lead to an increase in [Ca²⁺]_i,¹⁵³ which has been shown to relate to insulin resistance.¹⁵⁰ Furthermore, oral Mg²⁺ supplementation has been shown to improve insulin-mediated glucose uptake in type II diabetic patients.¹⁵⁴ Recently, using nuclear magnetic techniques, our investigative group has shown that IGF-1, like insulin, increases tissue [Mg²⁺]_i levels (Fig 6). These collective observations suggest that both elevations in [Ca²⁺]_i and depletions in [Mg²⁺]_i may contribute to resistance to vascular vasodilatory actions of insulin/IGF-1, leading to enhanced peripheral vascular resistance associated with insulin resistance.^{37 38 39 40 41 68}

Data have been garnered suggesting that the ability of insulin and IGF-1 to modulate the vascular NO system may be decreased in states of insulin resistance, thereby contributing to the increased incidence of hypertension in obese persons, type II diabetic patients, and some persons with essential hypertension.^{37 38 39 40 41} As previously noted, both insulin and IGF-1 stimulate production of NO by both endothelial cells and VSMCs,^{13 14 37 38 39 40} by stimulating both cNOS and iNOS activity (Fig 6). Furthermore, resistance to the vascular actions of insulin and IGF-1 is induced by the NO synthesis inhibitor L-NMMA.^{37 38 39 40 97 106} Acute reduction of leg blood flow with L-NMMA results in a 25% reduction in insulin-mediated leg glucose uptake, an effect independent of changes in insulin or glucose concentrations or adrenergic interaction.⁴⁰ We have recently observed that hyperglycemia tends to attenuate both IGF-1–stimulated and estradiol-stimulated NO production in cultured endothelial cells (Fig 1). Thus, impairment of insulin/IGF-1–mediated vasodilation in states of insulin resistance could contribute to both elevated blood pressures and reduced glucose uptake in insulin-sensitive tissues in these patients.

	Role of Hyperinsulinemia/Insulin Resistance in Pathogenesis of Atherosclerotic Disease

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 
Four large prospective studies have shown that hyperinsulinemia is a predictor of CAD,^{43 44 83 155} with a few prospective reports not demonstrating such a relationship.^{156 157} The greatest association of hyperinsulinemia with CAD has been found in Finland, in a population with a very high frequency of CAD.⁴³ A recent report⁸³ of a prospective investigation of 2103 men from Quebec clearly showed that high fasting insulin concentrations are an independent predictor of CAD. This important study used an insulin assay without cross-reactivity with proinsulin, thus avoiding that confounding influence.⁵⁴ Several recent studies have shown a relationship between carotid wall atherosclerotic lesions and insulin levels/resistance.^{75 76 77 78 80} Thus, hyperinsulinemia does appear to be a predictor for the development of CAD and stroke.

We have observed the role of cyclic and sustained stretch in VSMC IGF-1 and NO expression. Cyclic stretch causes VSMC thymidine uptake and IGF-1 and NO production secretion. Addition of IGF-1 antibodies to the growth medium inhibits stretch-induced growth (Fig 7). However, the role of PDGF in VSMC autocrine growth cannot be overlooked, since other investigators have demonstrated that similar stretch paradigms induced PDGF expression/secretion. Blocking PDGF action with anti-PDGF antibodies attenuates, but does not abolish, stretch-induced growth. Given that PDGF increases VSMC IGF-1 expression, it is becoming increasingly clear that autocrine VSMC growth is under the control of several locally produced factors, including IGF-1 and NO (ie, stimulation/inhibition). Thus, it is likely that many of the growth and atherosclerotic effects that have been attributed to insulin are mediated through an IGF-1 receptor either directly by IGF-1 or indirectly by high concentrations of insulin.

	Selected Abbreviations and Acronyms

 

Ang I, Ang II = angiotensin I and II CAD = coronary artery disease cNOS, iNOS = constitutive, inducible NOS IGF-1 = insulin-like growth factor I L-NAME = NG-nitro-L-arginine methyl ester L-NMMA = NG-monomethyl-L-arginine NO = nitric oxide NOS = NO synthase PDGF = platelet-derived growth factor SMBF = skeletal muscle blood flow SNS = sympathetic nervous system VSMC = vascular smooth muscle cell

	Acknowledgments

 
This work was supported by a VA research grant, National Institutes of Health grant R01-HD-24497-06, and the American Heart Association. The author wishes to thank Paddy McGowan for preparation of this manuscript.

This presentation and publication is one of a long-standing Clinical Conference Series supported by an educational grant-in-aid from the Health Sciences Service of Merck & Co and Astra-Merck Pharmaceuticals.

Received September 24, 1996; first decision September 26, 1996; accepted September 26, 1996.

	References

Top Introduction Hemodynamic Actions of Insulin... Role of NO in... Effects of Insulin and... Activation of the Sympathetic... Actions of Insulin/IGF-1... Role of Insulin Resistance... Role of Hyperinsulinemia/Insulin... References

 

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