Role of Ca2 in Pulmonary Vasoconstriction and Pasmc Proliferation

Contraction of vascular smooth muscle permits active changes in diameter and wall tension of pulmonary blood vessels. An increase in cytoplasmic free Ca2+ concentration ([Ca2+]cyt) in PASMC is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation. When [Ca2+]cyt rises, Ca2+ binds to calmodulin (CaM), and then activates myosin light chain kinase that phosphorylates the myosin light chain. The phosphorylation increases the myosin ATPase activity that hydrolyzes ATP to release energy. The subsequent cycling of the myosin cross-bridges produces displacement of the myosin filament in relation to the actin filament and causes contraction (96).

In isolated PA rings (Fig. 1Aa), removal of extracellular Ca2+ almost abolished the sustained pulmonary vasoconstriction induced by high (which induces membrane depolarization by shifting the equilibrium potential for K+) (Fig. 1Ab) and markedly inhibited vasoconstriction induced by phenylephrine (PE, which activates a-adrenogic receptors in the plasma membrane) (Fig. lAc). In the absence of extracellular Ca2+, application of vasoactive substances, such as PE, to the PA rings induces a transient contraction followed by a small sustained contraction (Fig. 1Ac). There results suggest that membrane depolarization-mediated pulmonary vasoconstriction completely depends on extracellular Ca2+, while the agonist-mediated pulmonary vasoconstriction is composed of at least three components: a transient contraction and a small sustained contraction that are not dependent on extracellular Ca2+, and a large sustained contraction that is dependent of extracellular Ca2+. The extracellular Ca2+-independent transient and sustained contractions are due to Ca2+ release from the intracellular stores to the cytosol and to Ca2+ sensitization of the contractile apparatus (or a Ca2+-insensitive mechanism), respectively (57, 96). The Ca2+-dependent sustained contraction is due to a rise in [Ca2+]cyl as a result of Ca2+ influx through sarcolemmal Ca2+-permeable channels.

Intracellular Ca2+ not only serves as a major trigger for vascular smooth muscle contraction (96), a rise in [Ca2+]cyt is also essential for cell proliferation (8), migration (73), and gene expression (26). Ca2+ diffuses quickly between the cytosol and nucleus (3). In the cell cycle of mammalian cells, there are at least four Ca2+/CaM-sensitive steps (Fig. IBa): a) transition from G0 (resting state) to G, phase (the beginning of DNA synthesis), b) transition from G, to S phase (an interphase during which replication of the nuclear DNA occurs), c) transition from G2 to M phase (mitosis), and d) mitosis (M phase) (8). Maintenance of sufficient Ca2+ within the intracellular Ca2+ stores is required for cell growth; depletion of the SR Ca2+ store induces growth arrest (94) and may trigger apoptosis (32).

Vasoconstriction Steps

Figure 1, Extracellular Ca2+ is required forpulmonary vasoconstriction and PASMC proliferation. A: Isometric tension was measured in isolated PA rings from rats (a). Vasoconstriction was induced by applying 40 mM K+ (40K, b) or 2 jiM phenylephrine (PE, c) in the presence or absence (OCa) of 1.8 mM CaJ+. B: Ca2+ dependence of the cell cycle (b). A time course (b) of human PASMC proliferation in the presence of serum (5% FBS), growth factors, and extracellular CaJ+. Chelation of extracellular Ca2+ with 2 mM EDTA inhibits PASMC proliferation (c). BM, smooth muscle basal medium; GM, serum- and growth factor-supplemented growth medium. ***P<0.001 vs. GM (Reproduced from Refs. 28 and 52).

Figure 1, Extracellular Ca2+ is required forpulmonary vasoconstriction and PASMC proliferation. A: Isometric tension was measured in isolated PA rings from rats (a). Vasoconstriction was induced by applying 40 mM K+ (40K, b) or 2 jiM phenylephrine (PE, c) in the presence or absence (OCa) of 1.8 mM CaJ+. B: Ca2+ dependence of the cell cycle (b). A time course (b) of human PASMC proliferation in the presence of serum (5% FBS), growth factors, and extracellular CaJ+. Chelation of extracellular Ca2+ with 2 mM EDTA inhibits PASMC proliferation (c). BM, smooth muscle basal medium; GM, serum- and growth factor-supplemented growth medium. ***P<0.001 vs. GM (Reproduced from Refs. 28 and 52).

The Ca2+/CaM-dependent propelling and progression of the cell cycle are regulated by both cytoplasmic and nuclear [Ca2+] (31). For example, a rise in [Ca2+]cyt activates Ras and CREB, two transcription factors that are involved in cell proliferation (31). An increase in nuclear [Ca2+] activates AP-1, a family of transcription factors (e.g., c-Fos, c-Jun) that promote cell proliferation (8).

Furthermore, maintaining a sufficient Ca2+ in the sarcoplasmic (SR) or endoplasmic (ER) reticulum (an organelle in which protein and lipid synthesis and sorting take place) is also required for cell growth (94).

The Ca2+ dependence of cell growth can be exhibited by examining whether removal (or chelation) of extracellular Ca2+ or depletion of Ca2+ in the SR affects cell proliferation in the presence of serum and growth factors. As shown in Figure IB, chelation of extracellular Ca2+ significantly inhibits human PASMC growth in media containing 5% fetal bovine serum and growth factors (epidermal growth factor, platelet-derived growth factor, endothelial growth factor, and/or insulin). Depletion of intracellularly-stored Ca2+ in the SR using thapsigargin or cyclopiazonic acid (CPA) further inhibits PASMC growth (28, 94). The synergistically inhibitory effects of removal of extracellular Ca2+ and depletion of stored Ca2+ on PASMC proliferation indicate that both extracellular Ca2+ and stored Ca2+ are required for cell growth, and suggest that Ca2+ influx is an important mechanism to maintain sufficient Ca2+ in the SR. These results provide compelling evidence that a constant Ca2+ influx and a sufficient level of Ca2+ in the SR are both required for PASMC to proliferate.

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