Abstract-We investigated the role of heme oxygenase (HO)-1 in the development of hypoxia-induced pulmonary hypertension. HO catalyzes the breakdown of heme to the antioxidant bilirubin and the vasodilator carbon monoxide. Hypoxia is a potent but transient inducer of HO-1 in vascular smooth muscle cells in vitro and in the lung in vivo. By using agonists of HO-1, we sustained a high expression of HO-1 in the lungs of rats for 1 week. We report that this in vivo enhancement of HO-1 in the lung prevented the development of hypoxic pulmonary hypertension and inhibited the structural remodeling of the pulmonary vessels. The mechanism(s) underlying this effect may involve a direct vasodilating and antiproliferative action of endogenous carbon monoxide, as well as an indirect effect of carbon monoxide on the production of vasoconstrictors. These results provide evidence that enhancement of endogenous adaptive responses may be used to prevent hypoxia-induced pulmonary hypertension. (Circ Res. 2000;86:1224-1229.)Key Words: vascular remodeling Ⅲ gene expression Ⅲ hypoxia H eme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to biliverdin and subsequently to bilirubin. The reaction catalyzed by HO is the major source of carbon monoxide (CO) in the body, which is increasingly recognized as a physiologically important molecule rather than a toxic waste product. 1 There are 3 known isoforms of HO. HO-1 is inducible, 2 whereas HO-2 and HO-3 are constitutively expressed. 3,4 HO-3 is highly homologous to HO-2 but has not been characterized fully. HO-2 is the predominant form expressed in the central nervous system, where CO is thought to act as a neurotransmitter via the soluble guanylate cyclase/cGMP pathway. 5 HO-1, the inducible form of the enzyme, is highly expressed in erythropoietic tissues, where its function is heme degradation, but it is also expressed in vascular smooth muscle cells (SMCs), 6 where its role may include regulation of vascular tone. Several lines of investigation provide evidence that CO may be a physiological regulator of cellular interactions in the vasculature, acting as a direct and indirect vasodilator; directly, CO acts via activation of soluble guanylate cyclase and elevation of cGMP, as in rat aortic and coronary vascular SMC preparations 6,7 as well as in dog femoral, carotid, and coronary arteries. 8 Indirectly, SMC-derived CO may cause SMC relaxation by inhibiting the hypoxic induction of the vasoconstrictors endothelin-1 (ET-1) and platelet-derived growth factor-B (PDGF-B) in adjacent endothelial cells. 9 In addition to its vasodilatory actions, CO was shown to inhibit SMC proliferation by regulating the cell cycle-specific transcription factor E2F-1, 10 as well as the expression of the mitogens ET-1 and PDGF-BB in culture. 9 A variety of cellular stressors, such as heat shock, oxidative stress, heavy metals, and hemoproteins, induce HO-1. 11-13 Therefore, a protective/antioxidant role has been proposed for HO-1, as well as its enzymatic product, bilirubin. 14 We found t...
We identified the cell surface glycoprotein Thy-1 on the endothelium of newly formed blood vessels in four models of angiogenesis in adult rats. Anti-Thy-1 staining showed that Thy-1 was upregulated in adventitial blood vessels after balloon injury to the carotid artery. Preabsorption with a rat Thy-1-Ig fusion construct eliminated all immunoreactivity and thus confirmed the specificity of the Thy-1 staining. Thy-1 was also expressed in the endothelium of small blood vessels formed after tumor implantation in the cornea, in periureteral vessels formed after ligation of the renal artery, and in small blood vessels of the uterus formed during pregnancy. In contrast with its expression during adult angiogenesis, Thy-1 was not expressed in the endothelium of blood vessels during embryonic angiogenesis. In vitro, the inflammatory cytokines interleukin-1 and tumor necrosis factor-upregulated Thy-1 mRNA by 8-and 14-fold, respectively. Vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-, and platelet-derived growth factor-BB had no effect on Thy-1 mRNA. Thus, Thy-1 appears to be a marker of adult but not embryonic angiogenesis. The upregulation of Thy-1 by cytokines but not growth factors indicates the importance of inflammation in the pathogenesis of adult angiogenesis. (Circ Res. 1998;82:845-851.) Key Words: endothelium interleukin-1 tumor necrosis factor inflammation angiogenesis
Vascular smooth muscle and the associated connective tissue matrix are central to blood vessel integrity and function, and activation of vascular smooth muscle cells is characteristic of arteriosclerosis and hypertension. After vessel wall injury, smooth muscle cells are transformed from a contractile, quiescent phenotype to a proliferative, migratory phenotype that secretes abundant extracellular matrix (1). Vascular smooth muscle cells are subject to complex regulation by soluble extracellular signals provided by growth factors, cytokines, and vasoactive agents as well as cell-cell and cell-matrix interactions (1). Therefore, factors controlling smooth muscle cell behavior, including migration, proliferation, and lipid metabolism, are critical to the pathogenesis of cardiovascular disease. Cell surface signal transduction and adhesion molecules such as vascular cell adhesion molecule-1 (2) and the 1 and 3 integrins (3, 4) have been implicated in the modulation of smooth muscle cell function. Previous studies from our laboratory indicate that the proteoglycan CD44 may also mediate vascular smooth muscle cell activation during vascular remodeling (5).The CD44 transmembrane glycoprotein exists in a variety of isoforms generated by alternative splicing of one (or more) of 10 variable exons in the extracellular domain (6, 7). CD44 is the principal cell receptor for hyaluronic acid (8) and interacts with other extracellular matrix molecules including osteopontin, collagen, and fibronectin (9, 10). Present on many cell types, CD44 has been correlated with cell proliferation (11, 12) and oncogenic transformation (13). Ligation of CD44 stimulates cytokine release by monocytes/macrophages (14, 15), and it may modulate T lymphocyte activation signals (16,17). In a variety of cell systems CD44 imparts a novel cellular adhesive and/or migratory phenotype to transfected cells (9,18,19), and an isoform containing the sixth variable exon (v6) confers metastatic potential to rat pancreatic carcinoma cells (20). The importance of CD44 in vivo has also been demonstrated in a mouse model in which an antisense CD44 transgene is expressed selectively under the control of a keratinocyte-specific promoter (21). Suppression of CD44 expression inhibits keratinocyte proliferation and results in abnormal hyaluronate metabolism in the skin. Moreover, CD44 is induced on smooth muscle cells after vascular injury, and it may mediate the proliferative effects of hyaluronate (5).Our laboratory has developed a mouse model of transplantassociated arteriosclerosis in which a carotid artery loop is transplanted between inbred strains in syngeneic and allogeneic combinations (22). Lesion development depends on an acquired immune response and begins with infiltration of inflammatory cells, after which follows accumulation of smooth muscle cells in the neointima (23). In the present study we evaluated CD44 cell surface protein expression in vivo during the pathogenesis of transplant arteriosclerosis in order to understand the role of CD44 in modula...
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