血管平滑肌的生长

Vascular Smooth Muscle Growth: Autocrine Growth Mechanisms BRADFORD C. BERK Center for Cardiovascular Research, University of Rochester, Rochester, New York I. Introduction 999 II. Physiological Processes That Require Vascular Smooth Muscle Cell Growth 1000 A. Development 1000 B. Injury 1001 C. Remodeling 1001 III. Different Types of Vascular Smooth Muscle Cell Growth 1002 A. VSMC heterogeneity 1002 B. Hyperplasia 1004 C. Hypertrophy 1004 D. Antiapoptotic effects 1005 IV. Autocrine Growth Factors and Receptors 1005 A. Secreted factors coupled to tyrosine kinase receptors 1005 B. Secreted factors coupled to G protein-coupled receptors 1009 C. Secreted factors coupled to other receptors 1012 D. Other proteins involved in autocrine growth mechanisms 1015 E. Nonprotein stimuli that activate VSMC autocrine growth mechanisms 1017 V. Conclusions: Angiotensin II-Mediated Events as a Paradigm for Autocrine Growth Mechanisms 1020 Berk, Bradford C. Vascular Smooth Muscle Growth: Autocrine Growth Mechanisms. Physiol Rev 81: 999–1030, 2001.—Vascular smooth muscle cells (VSMC) exhibit several growth responses to agonists that regulate their function including proliferation (hyperplasia with an increase in cell number), hypertrophy (an increase in cell size without change in DNA content), endoreduplication (an increase in DNA content and usually size), and apoptosis. Both autocrine growth mechanisms (in which the individual cell synthesizes and/or secretes a substance that stimulates that same cell type to undergo a growth response) and paracrine growth mechanisms (in which the individual cells responding to the growth factor synthesize and/or secrete a substance that stimulates neighboring cells of another cell type) are important in VSMC growth. In this review I discuss the autocrine and paracrine growth factors important for VSMC growth in culture and in vessels. Four mechanisms by which individual agonists signal are described: direct effects of agonists on their receptors, transactivation of tyrosine kinase-coupled receptors, generation of reactive oxygen species, and induction/secretion of other growth and survival factors. Additional growth effects mediated by changes in cell matrix are discussed. The temporal and spatial coordination of these events are shown to modulate the environment in which other growth factors initiate cell cycle events. Finally, the heterogeneous nature of VSMC developmental origin provides another level of complexity in VSMC growth mechanisms. I. INTRODUCTION Vascular smooth muscle cells (VSMC) are among the most plastic of all cells in their ability to respond to different growth factors. Specifically, VSMC may prolifer- ate (hyperplasia with an increase in cell number), hyper- trophy (an increase in cell size without change in DNA content), endoreduplicate (an increase in DNA content and usually size), and undergo apoptosis. Among the mechanisms utilized by VSMC to mediate these varying cellular responses are autocrine and paracrine growth pathways. An autocrine growth mechanism is one in which the individual cell, in response to a growth factor, synthesizes and/or secretes a substance that stimulates that same cell type to undergo a growth response. A paracrine growth mechanism is one in which the individ- ual cells responding to the growth factor synthesize and/or secrete a substance that stimulates neighboring PHYSIOLOGICAL REVIEWS Vol. 81, No. 3, July 2001 Printed in U.S.A. http://physrev.physiology.org 9990031-9333/01 $15.00 Copyright © 2001 the American Physiological Society cells of another cell type. In many situations, autocrine and paracrine growth mechanisms occur simultaneously. It is very difficult to separate these pathways in vivo, so in this review the focus is on VSMC autocrine growth mech- anisms. When there is solid evidence for interactions between autocrine and paracrine mechanisms, an effort will be made to delineate the separate and specific roles. The concept of VSMC auto/paracrine growth was first proposed in the late 1970s as a result of work in the laboratories of Gospodarowicz et al. (101), Harker and Ross (120), Karnovsky and co-workers (41), and Chamley- Campbell et al. (43). Dzau (70) and Nilsson et al. (230) were the first to use the term autocrine growth to de- scribe increased expression of VSMC growth factors by VSMC. It has now become clear that almost all VSMC growth factors elicit auto/paracrine growth pathways. However, recent data indicate that many other stimuli that modulate VSMC function including extracellular ma- trix, biomechanical forces, reactive oxygen species (ROS), lipids, and other proteins alter VSMC growth by inducing auto/paracrine growth mechanisms. The major questions that will be addressed in this review are as follows: 1) Why do VSMC utilize auto/paracrine growth mechanisms? 2) Why are so many growth factors induced by a single stimulus (in other words, what is the reason for redundant growth mechanisms)? To answer these questions the following issues are addressed below. First, the physiological processes that require VSMC growth are discussed to provide insight into how these differing sit- uations may have influenced the development of auto/ paracrine growth. The concept to be advanced is that temporal, spatial, and pathophysiological specific situa- tions have mandated a coordinated and complex series of growth responses. Second, the “plastic” nature of VSMC growth is presented to illustrate the diversity of these responses. The concept to be discussed is that there is a correlation between the multiple auto/paracrine growth mechanisms, the presence of VSMC heterogeneity, and the varied nature of VSMC growth responses. Third, the individual growth factors that have been identified as mediating auto/paracrine growth are discussed. Fourth, the stimuli that elicit the synthesis and/or release of these factors are presented. Finally, an integrated analysis of the autocrine mechanisms utilized by angiotensin II are discussed as a model that places the relative roles of different factors into a pathophysiologically important context. II. PHYSIOLOGICAL PROCESSES THAT REQUIRE VASCULAR SMOOTH MUSCLE CELL GROWTH The concept to be developed in this section is that temporal, spatial, and pathophysiologically specific situa- tions have mandated a coordinated and complex series of VSMC growth responses. The ability of VSMC to be plastic in their growth responses is a key mechanism by which the vasculature responds to hemodynamic, developmen- tal, and injurious stimuli. Fundamental to our understand- ing of the role of auto/paracrine growth mechanisms in VSMC growth is relating VSMC growth to important bio- logical functions of the blood vessel. Examples of biolog- ical processes during which VMSC would be expected to grow include vessel development, the vascular response to tissue injury, and vessel remodeling in response to changes in tissue demand. Pathological examples include atherosclerosis, hypertension, restenosis postangioplasty, and vasculitis. In all situations it is clear that interactions between endothelial cells and VSMC as well as between VSMC and other cells (e.g., fibroblasts, dendritic cells, and inflammatory cells) within the vessel wall determine the nature of the growth response. A. Development The process of vessel development, growth, and re- modeling provides important insights into mechanisms that regulate vessel function and VSMC growth in the adult. The process of blood vessel formation in the em- bryo is termed angiogenesis, which involves the differen- tiation of angioblasts into endothelial cells (EC) that as- semble into a primitive vascular network. Subsequently, growth and remodeling of the network occurs, a process termed angiogenesis. In the adult, three processes can be used to form new vessels: vasculogenesis (rarely), angio- genesis, and arteriogenesis. Arteriogenesis has frequently been termed collateral vessel growth and refers to en- largement of small arterioles into larger vessels. Because these processes have been extensively reviewed (40), this section focuses primarily on VSMC developmental fea- tures. The first cell responsible for the formation of the primordial blood vessel tube is the EC (130). Once the primitive EC tubes are formed, the endothelium secretes factors that lead to the recruitment and/or induction of primordial smooth muscle, a process termed vascular myogenesis. Several recent reviews have carefully docu- mented the current state of knowledge regarding the dif- ferentiation and growth of VSMC to form the tunica media (40, 130). This may occur by 1) angiopoietin-1-mediated production of VSMC inducing factor(s) by EC that causes differentiation from the mesoderm; 2) an autocrine mech- anism in which angiopoietin-1 causes EC to differentiate into VSMC (transdifferentiation) (61) as well as transdif- ferentiation from bone marrow precursors or macro- phages; 3) transformation of epicardial cells to form the coronary VSMC (130, 328); and 4) differentiation of the mesectoderm of the neural crest into VSMC (18, 264). It is 1000 BRADFORD C. BERK Volume 81 important to note that VSMC have a complex origin de- pending on their location. For example, VSMC of coro- nary veins are derived from atrial myocardium while VSMC of coronary arteries are derived from epicardium (62). This suggests that individual growth factors and their receptors will have different effects on VSMC growth and differentiation in specific vascular beds. This is an important caveat for many of the discussions of autocrine VSMC growth below. The process by which VSMC contribute to vessel formation may be divided into three components: differ- entiation, recruitment and growth, and remodeling. Dif- ferentiation of VSMC involves transcriptional events me- diated by the serum response factor, Prx-1 and Prx-2, CRP2/SmLIM, and members of the HOX, MEF2, and GATA family. Factors that stimulate VSMC from meso- derm have been best studied, and candidate mediators include platelet-derived growth factor (PDGF) and trans- forming growth factor (TGF)-b (98, 130). Factors that act as chemoattractants for VSMC include PDGF-BB and epi- dermal growth factor (EGF). Studies in mice lacking PDGF-BB and PDGFR-b (124) suggest that PDGFR-b ex- pressing VSMC progenitors form around certain vessels by a process independent of PDGF-BB. These cells then undergo angiogenic sprouting and vessel enlargement in a process that is both PDGF-BB dependent and indepen- dent depending on tissue context. The nature of the growth factors secreted by embryonic EC that stimulate VSMC proliferation remain to be identified. In addition, it is possible that VSMC themselves, upon interacting with embryonic EC, activate auto/paracrine pathways that lead to VSMC hyperplasia. Important roles for TGF-b1 and endoglin (an endothelial TGF-b binding protein) have been established in that they stimulate VSMC differentia- tion and extracellular matrix deposition and strengthen EC-VSMC interactions (63, 177). Endothelin (ET)-1 ap- pears to have an important role in migration and differ- entiation of VSMC from neural crest cells (342). Other growth factors with important roles in differentiation and growth include tissue factor, heparin binding EGF-like factor (HBEGF), and the Eph-Ephrin system. Remodeling during development involves transcription, growth fac- tors, and physical forces. Aortic arch abnormalities as an example of defective remodeling have been demonstrated in knockout mice that include MFH-1, dHand or Msx1, pax-3, Prx1, retinoic receptors, the neurofibromatosis type-p1 gene product, Wnt-1, connexin 43, and ET-1. Fi- nally, physical forces, notably the initiation of blood flow, may have important effects to stimulate the primitive vessel to remodel especially via regulation of nitric oxide production. In summary, it is clear that multiple transcrip- tional and growth factor-related events participate in the process by which VSMC create the vascular media; many of these same processes occur in the adult during arte- riogenesis and angiogenesis. B. Injury Perhaps the best studied situation in which VSMC growth occurs is after injury to the blood vessel. While the rat carotid balloon injury model has been investigated extensively for many years (49), the pattern of events that leads to vessel repair and intimal thickening appears sim- ilar in other species (pig, mouse, nonhuman primate, and human) and other arteries (aorta, iliac, femoral, and bra- chial). Many candidate molecules that regulate VSMC growth have been studied in the rat carotid injury model by use of pharmacological and gene therapy approaches. Results suggest important roles for the renin-angiotensin system, catecholamines, ET-1, natriuretic peptides, thrombin, PDGF, TGF-b and other activins (242), fibro- blast growth factor (FGF), and oxidative stress among other stimuli (100, 163). Recent results with transgenic knockout mice provide further support for these mole- cules as regulators of VSMC growth after injury as well as nitric oxide (269) and the estrogen receptor (134). Despite this long history, the exact origin of the cell type that leads to formation of the neointima (dedifferentiated VSMC, VSMC progenitor cell, or myofibroblast) remains unknown. The mechanisms by which VSMC growth is halted and cell number regulated remain unclear. Much progress has been made in mechanisms of VSMC apopto- sis, but how the size of blood vessels and the media in particular are regulated remains to be defined. Finally, it is important to note that both autocrine and paracrine growth mechanisms are essential for formation of the neointima. In this review emphasis is on autocrine VSMC growth mechanisms, acknowledging important paracrine contributions from endothelial cells, monocyte/macro- phages, fibroblasts, dendritic cells, and polymorphonu- clear leukocytes. C. Remodeling Vascular remodeling (Fig. 1) is a physiological re- sponse to alterations in flow, pressure, and atherosclero- sis. Remodeling involves changes in VSMC growth and migration as well as alterations in vessel matrix (214). Remodeling may be classified as proposed by Mulvany based on the nature of changes in vessel diameter (inward or outward) and by changes in mass (increased 5 hyper- trophic, decreased 5 atrophic, no change 5 eutrophic) (214). As an example “eutrophic outward” remodeling would be an increase in lumen diameter without change in amount or characteristics of the vessel such as may occur with increased flow and atherosclerosis. In con- trast, “hypertrophic inward” remodeling would be defined as a decrease in lumen diameter with increased wall thickness such as may occur with increased pressure. It has been best studied in resistance vessels during hyper- July 2001 VASCULAR SMOOTH MUSCLE GROWTH 1001 tension. During chronic hypertension, there is an increase in vessel wall thickness hypothesized to normalize wall stress. Physical forces (wall stress and cell stretch), au- tocrine growth mechanisms, and paracrine growth mech- anisms (EC actions on VSMC) stimulated by the hyper- tensive environment appear causative. In response to changes in blood flow, remodeling appears to be fundamentally dependent on the presence of an intact endothelium as shown by Langille and co- workers (173, 174) and by Kohler et al. (155). Because flow-induced remodeling would be expected teleologi- cally to be mediated by changes in vessel tone and hence diameter, candidate mediators are vasoactive molecules. Among these, nitric oxide [produced by endothelial nitric oxide synthase (eNOS)] appears to play a predominant role. Recent studies show that ;70% of flow-dependent outward remodeling is due to EC nitric oxide production as determined by inhibiting production of nitric oxide with eNOS inhibitors (317). During inward remodeling in response to decreased flow, there is a coordination of in- creased VSMC apoptosis and decreased VSMC proliferation to effect the decrease in vessel wall mass that occurs (47). An important role for monocytes has been elucidated in remodeling, especially in response to ischemia such as oc- curs after occlusion of a supply artery (277). In response to increases in flow, EC express monocyte chemotactic pep- tide-1 (MCP-1) and monocyte adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1). The monocytes are recruited to the vessel and infiltrate and digest the me- dia. The EC are activated by monocytes and express basic FGF (bFGF), PDGF-BB, and TGF-b. These growth factors then lead to VSMC growth and vessel enlargement. In response to increased pressure, remodeling ap- pears to be due to activation of autocrine mechanisms that stimulate VSMC growth and changes in vessel wall matrix (123, 213, 215). As discussed in greater detail in section IV, many VSMC growth factors have been impli- cated in the growth and remodeling of hypertensive ves- sels including PDGF (227, 274), TGF-b, insulin-like growth factor I (IGF-I) and the IGF-I binding proteins (7), and hepatocyte growth factor (221). Paracrine mecha- nisms that are important in hypertension include in- creased production of ET-1 and angiotensin II by the endothelium. III. DIFFERENT TYPES OF VASCULAR SMOOTH MUSCLE CELL GROWTH The concept to be discussed is that there is a corre- lation between the multiple autocrine growth mecha- nisms, the presence of VSMC heterogeneity, and the di- verse nature of VSMC growth responses. VSMC, like other mesenchymal cells, differentiate and then exist in a G0 growth-arrested state. In general, VSMC have resembled most other cell types in the mechanisms for cell cycle entry, progression, and arrest. Several recent reviews have discussed the mechanisms by which VSMC exit the G0 state and enter the cell cycle (33). The reader is referred to these reviews for further information. A. VSMC Heterogeneity Although many investigators assume that smooth muscle cells in the vessel wall are morphologically simi- lar, it has become clear that they are phenotypically and functionally heterogeneous, which has obvious conse- FIG. 1. Vascular remodeling. 1002 BRADFORD C. BERK Volume 81 quences for responses to various growth factors. A basic question is whether this is due to differences in origin or to spatiotemporal heterogeneity in expression of differ- entiation markers due to local environmental and hor- monal factors. As discussed below, both developmental and environmental factors influence VSMC heterogeneity. It is important to note that while the medial layer of the vessel is highly enriched in VSMC, other cell types may coexist in this layer. This has important implications since migration and growth of medial cells to form a neointima is an important pathological process in athero- sclerosis and restenosis. By implication, not all cells that are present in the neointima may be VSMC. For example, Frid et al. (84) were able to isolate at least four pheno- typically unique cell subpopulations from the inner, mid- dle, and outer compartments of the arterial media. Differ- ences in cell phenotype were demonstrated by morphological appearance and by differential expression of muscle-specific proteins. The isolated cell subpopula- tions exhibited markedly different growth capabilities. Two SMC subpopulations grew slowly in 10% serum and were quiescent in plasma-based medium. The other two cell subpopulations, exhibiting nonmuscle characteris- tics, grew rapidly in 10% serum and proliferated in plas- ma-based medium. These differences in growth were sub- sequently related to production of autocrine growth factors (85). Similar VSMC heterogeneity was observed for human VSMC (17). Two morphological phenotypes of VSMC are usually defined, namely, the epithelioid and the spindle-shaped cell (29). Functionally these phenotypes have been suggested to correlate with the synthetic and contractile cell