Angiotensin II induces proliferation of human cerebral artery smooth muscle cells through a basic fibroblast growth factor (bFGF) dependent mechanism

Wang, Zhongbiao; Rao, Pulipaka J.; Shillcutt, Samuel D.; Newman, Walter H.

doi:10.1016/j.neulet.2004.09.068

Cited by 20 publications

(16 citation statements)

References 13 publications

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“…Activated VSMCs contribute to thickened vessel wall and vascular remodeling through accumulation in intima and medium (1,31). As expected, we observed aortic hypertrophic remodeling during hypertension, characterized by intima-media thickening and lumen loss.…”

Section: Discussionsupporting

confidence: 86%

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Zhang

Xie

Wang

et al. 2010

Journal of Biological Chemistry

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The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-␥ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-␥ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, ␣-smooth muscle actin (␣-SMA) and smooth muscle 22␣ (SM22␣), and enhanced proliferation and migration. PPAR-␥ overexpression rescued the expression of ␣-SMA and SM22␣, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-␥ silencing exerted the opposite effect. Activating PPAR-␥ using rosiglitazone in vivo up-regulated aortic ␣-SMA and SM22␣ expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-␥ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-␥ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-␥ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-␥ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-␥ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.Hypertension and hypertension-induced vascular remodeling underlie numerous cardiovascular disorders. Activated vascular smooth muscle cells (VSMCs) 2 are essential contributors to this vascular remodeling (1). Unlike other muscle cells, VSMCs do not terminally differentiate. They can switch from a differentiated phenotype (also known as contractile or quiescent phenotype) to a dedifferentiated phenotype (also known as synthetic or activated phenotype) in response to vascular injury. In this process, VSMCs regain their proliferative and migratory capacities, secrete matrix proteins, and down-regulate smooth muscle contractile proteins, such as ␣-smooth muscle actin (␣-SMA), smooth muscle 22␣ (SM22␣), smooth muscle myosin heavy chain, and calponin (2). Although this phenotypic modulation is undoubtedly required for vascular repair, inappropriate modulation is associated with increased vascular resistance and aggravates vascular injury. However, despite intensive research efforts, the precise mechanisms underlying VSMC phenotypic modula...

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Section: Discussionsupporting

confidence: 86%

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Zhang

Xie

Wang

et al. 2010

Journal of Biological Chemistry

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“…This effect is not unexpected, because Ang II is able to activate a variety of intracellular pathways involved in SMC migration and proliferation (35)(36)(37). It should be noted that the proliferative effect seen here was limited to hemodynamically altered vessels.…”

Section: Discussionsupporting

confidence: 58%

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

Cunha

Martin-McNulty

Vincelette

et al. 2006

Journal of Lipid Research

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Two month old C57BL/6 mice were placed on three different diets: 1) normal diet (NC; 0.025% cholesterol), 2) hypercholesterolemic Western-type diet (HC-W; 0.2% cholesterol), and 3) hypercholesterolemic Paigen-type diet (HC-P; 1.25% cholesterol plus 0.5% cholic acid). At 6 months of age, the animals underwent ligation of the left carotid artery and were randomly assigned to vehicle (PBS, subcutaneous) or angiotensin II (Ang II; 1.4 mg/kg/ day, subcutaneous) treatment for 4 weeks. Low density lipoprotein-cholesterol levels were similarly increased in both HC diets (NC, 4 6 3 mg/dl; HC-W, 123 6 17 mg/dl; HC-P, 160 6 14 mg/dl). However, the levels of high density lipoprotein-cholesterol (HDL-C) were reduced only in animals fed the HC-P diet (NC, 82 6 6 mg/dl; HC-W, 79 6 7 mg/dl; HC-P, 58 6 7 mg/dl). In Ang II-treated mice, carotid artery ligation induced intimal smooth muscle cell proliferation to a similar extent in NC-and HP-W-fed animals. However, a significantly larger intimal area developed in ligated vessels from Ang II-treated mice fed the HC-P diet (3.6-fold higher than in Ang II-treated NC mice). Together, these results show the accelerating effect of mild hypercholesterolemia, reduced HDL-C levels, and Ang II on intimal hyperplasia after carotid artery ligation in mice. Proliferation of smooth muscle cell (SMCs) and migration into the intima is the hallmark of restenosis after vascular interventions (angioplasty, stent or vein graft placement) (1-3) and an important feature of preatherosclerotic lesions (4). It is well established that hypercholesterolemia accelerates atherosclerosis development; however, studies addressing the effect of circulating cholesterol on intimal SMC proliferation have yielded conflicting results. For instance, Theilmeier et al. (5) showed that hypercholesterolemia decreased the population of SMCs in atheromatous lesions in postangioplasty porcine coronary arteries. In contrast, in a recent study, Kahn et al. (6) observed accelerated angioplasty-induced intimal hyperplasia in aortas from hypercholesterolemic rabbits. In both studies, circulating levels of cholesterol were 9-and 18-fold higher than control levels, exceeding the pathophysiologic range of human hypercholesterolemia. Additionally, the concomitant development of spontaneous atheromatous plaque found in these studies adds another important level of interaction between macrophage/foam cell-derived mediators and SMC proliferation (7).In addition to changes in hemodynamic forces (e.g., low shear stress) (8) as predisposing factors for intimal hyperplasia development, locally produced neurohumoral mediators, particularly angiotensin II (Ang II) (9), may be equally important in determining such predisposition. Increased vascular levels of Ang II and the expression of its AT1 receptors were found in intimal SMCs of aortas from aging nonhuman primates (10) and in in-stent restenotic lesions of human coronary arteries (11). More importantly, in vitro studies showing synergism between lipoproteins and Ang II in inducing...

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“…(59) Finally, angiotensin II appears, at least in part, to exert its proangiogenic effects by upregulating other intracrine angiogenic factors, such as VEGF and bFGF. (60,61) Endothelin, an intracrine, is synthesized by endothelial cells and is angiogenic. Platelet derived growth factor (PDGF), an intracrine, probably is not directly mitogenic for endothelial cells but rather stimulates angiogenesis indirectly by upregulating other factors such as VEGF and bFGF.…”

Section: Other Intracrinesmentioning

confidence: 99%

An intracrine view of angiogenesis

Ré

Cook

2006

BioEssays

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Angiogenesis, the generation of new blood vessels from pre-existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain extracellular signaling peptides (whether hormones, growth factors, DNA-binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis ("intracrine reciprocity") are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor-induced angiogenesis and tissue differentiation.

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Angiotensin II induces proliferation of human cerebral artery smooth muscle cells through a basic fibroblast growth factor (bFGF) dependent mechanism

Cited by 20 publications

References 13 publications

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

An intracrine view of angiogenesis

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