Pharmacology of smooth muscle cell replication.

Abstract

The suggestion that smooth muscle cell proliferation contributes to hypertension, atherosclerosis, and restenosis after angioplasty has led to a growing interest in the use of drugs to inhibit this process. This review summarizes pharmacological studies of smooth muscle cell proliferation in vitro and in vivo and identifies specific mediators of proliferation that are implicated by drugs binding with high affinity to enzymes or receptors. (Hypertension 1992^0:713-736) KEY WORDS • atherosclerosis • growth substances • hypertension, essential • muscle, smooth, vascular T his review emphasizes agents that influence smooth muscle proliferation. Four overlapping categories of agents that could be discussed are growth factors, drugs with known pharmacological effects, endocrine hormones with growth regulatory properties, and intracellular mediators of replication. This review will concentrate on the last three categories. A great deal has already been written in other reviews about the growth factors, but the much longer list of possible targets discussed here has not been reviewed systematically. Moreover, a great deal is known about the pharmacology of some of the molecules in our review, so their therapeutic value in the treatment of conditions arising from smooth muscle replication is likely to be realized more quickly in a clinical sense than treatments based on the still very poorly understood pharmacology of growth factors. Pathology of Smooth Muscle ProliferationSmooth muscle proliferation has been implicated as playing a central role in atherosclerosis and hypertension.1 The evidence that smooth muscle cell proliferation occurs in these diseases is clear. As we will briefly review, however, evidence for a causal connection is not well established. Smooth Muscle Replication in HypertensionThe argument for a role of smooth muscle cell replication in hypertension is an outgrowth of the structural hypothesis of hypertension proposed by Folkow.2 Folkow explained that the ability of a resistance artery to restrict blood flow depends on the thickness of the vessel wall as well as on the size of the vessel lumen, the responsiveness of the wall to vasoactive stimuli, and the level of stimulation by vasoconstrictors. Folkow's idea is based on the simple physical fact that a thicker vessel wall will act as an amplifier, so that an equal vasoconstrictor stimulus will produce greater narrowing of the lumen in a hypotensive vessel than in a normotensive vessel. Studies of essential and secondary hypertension have confirmed that hypertensive vessel walls are thickened.3 Indeed, there is evidence that such structural changes precede any elevation in blood pressure,*-5 and, at least for the spontaneously hypertensive rat, wall thickening may depend on the increased sympathetic innervation that develops in the spontaneously hypertensive rat vessel wall within the first month of life. 5 -6 A correlation exists between the development of sympathetic innervation and the development of arterial medial hypertrophy in normotensive...

Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists

“…79,80 Therefore, it is not unexpected that the different classes of CCBs, including the dihydropyridines, do inhibit VSMC proliferation. 81 As an example, nifedipine inhibited VSMC proliferation in vitro and suppressed intimal thickening caused by balloon angioplasty-induced injury in rats in vivo. 82 Amlodipine is a potent inhibitor of VSMC proliferation and migration in vitro.…”

Catechins inhibit angiotensin II-induced vascular smooth muscle cell proliferation via mitogen-activated protein kinase pathway

“…Angiotensin II (Ang II) has been strongly implicated in the pathogenesis of hypertension, heart failure and arteriosclerosis characterized by abnormal proliferation and hypertrophy of the VSMC (Berk et al, 1989;Jackson and Schwartz, 1992;Horiuchi et al, 1999). Ang II regulates the activation of mitogenactivated protein kinases (MAPK) which are involved in the regulation of cell growth and division (Davis, 1993;Schmidt-Ott et al, 2000), through AT1 or AT2 receptors (Berk et al, 1989;Duff and Berk, 1995).…”

α1-Adrenergic Receptor Subtypes Differentially Control the Cell Cycle of Transfected CHO Cells through a cAMP-dependent Mechanism Involving p27

“…Plasma membrane receptors coupled to heterotrimeric G proteins (G protein-coupled receptor) a protein family with ϳ1,000 members, mediate a large variety of important physiological actions induced by hormones, neurotransmitters, and sensory signals. ␣ 1 -Adrenergic receptors (␣ 1 -ARs) 1 are members of the superfamily of G protein-coupled receptor and mediate the effects of the sympathetic nervous system, especially those effects related to the regulation of cellular hypertrophy and proliferation (1)(2)(3). There is substantial evidence indicating that stimulation of ␣ 1 -ARs by catecholamines generally enhances growth-related gene expression and cell growth in a variety of cells including cardiac myocytes, vascular smooth muscle cells, hepatocytes, and also adipocytes (4 -6).…”