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Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proliferation and matrix deposition in the wall of the pulmonary arterioles. We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and chemokines and is independent of tumor necrosis factor-␣ signaling. We have previously proposed a crucial role for heme oxygenase-1 (HO-1) in protecting cardiomyocytes from hypoxic stress, and potent anti-inflammatory properties of HO-1 have been reported in models of tissue injury. We thus established transgenic mice that constitutively express HO-1 in the lung and exposed them to chronic hypoxia. HO-1 transgenic mice were protected from the development of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.A cute hypoxia in the lung causes arteriolar vasoconstriction whereas prolonged hypoxia promotes proliferation and migration of vascular smooth muscle cells (VSMC) and extracellular matrix deposition in the arterial wall, a process known as vascular remodeling (1). These abnormalities are characteristic of pulmonary hypertension (2). Several clinical conditions characterized by lung inflammation have been linked to the development of chronic pulmonary hypertension (3). Interestingly, perivascular inflammatory cell infiltration as well as increased serum levels of proinflammatory cytokines, such as IL-1␤ and IL-6, have been reported in clinical cases of primary pulmonary hypertension (4, 5). However, little attention has been given up to now to the role of pulmonary inflammation in the pathogenesis of pulmonary hypertension induced by hypoxia.Heme oxygenase (HO; EC 1.14.99.3) catalyzes the oxidation of heme to carbon monoxide (CO) and biliverdin, which is then converted to bilirubin by biliverdin reductase. Three isoforms of HO have been identified: the inducible HO-1 and the constitutively expressed HO-2 and HO-3 (6, 7). Our previous in vitro data suggest that CO released by HO-1 confers protection against vasoconstriction and vascular remodeling induced by hypoxia (8 -10). More recently, Soares et al. have suggested antiinflammatory properties of HO-1 in a cardiac transplantation model, although the molecular mechanisms have not been fully elucidated (11). Our recent in vivo data using an HO-1 null mouse model suggest that HO-1 plays a central role in protecting the right ventricle from hypoxic pulmonary pressure-induced injury (12).In the present study, we established transgenic mice that overexpress HO-1 in the lung and exposed them to hypoxia to investigate the effects of HO-1 activity on the developmen...

Regulation of fetal growth is multifactorial and complex. Diverse factors, including intrinsic fetal conditions as well as maternal and environmental factors, can lead to intrauterine growth restriction (IUGR). The interaction of these factors governs the partitioning of nutrients and rate of fetal cellular proliferation and maturation. Although IUGR is probably a physiologic adaptive response to various stimuli, it is associated with distinct short- and long-term morbidities. Immediate morbidities include those associated with prematurity and inadequate nutrient reserve, while childhood morbidities relate to impaired maturation and disrupted organ development. Potential long-term effects of IUGR are debated and explained by the fetal programming hypothesis. In formulating a comprehensive approach to the management and follow-up of the growth-restricted fetus and infant, physicians should take into consideration the etiology, timing, and severity of IUGR. In addition, they should be cognizant of the immediate perinatal response of the growth-restricted infant as well as the childhood and long-term associated morbidities. A multi disciplinary approach is imperative, including early recognition and obstetrical management of IUGR, assessment of the growth-restricted newborn in the delivery room, possible monitoring in the neonatal intensive care unit, and appropriate pediatric follow-up. Future research is necessary to establish effective preventive, diagnostic, and therapeutic strategies for IUGR, perhaps affecting the health of future generations.

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and blood vessel remodeling. Its expression is up-regulated in vascular smooth muscle cells by a number of conditions, including hypoxia. Hypoxia increases the transcriptional rate of VEGF via a 28-base pair enhancer located in the 5-upstream region of the gene. The gas molecules nitric oxide (NO) and carbon monoxide (CO) are important vasodilating agents. We report here that these biological molecules can suppress the hypoxia-induced production of VEGF mRNA and protein in smooth muscle cells. In transient expression studies, both NO and CO inhibited the ability of the hypoxic enhancer we have previously identified to activate gene transcription. Furthermore, electrophoretic mobility shift assays indicated decreased binding of hypoxia-inducible factor 1 (HIF-1) to this enhancer by nuclear proteins isolated from COtreated cells, although HIF-1 protein levels were unaffected by CO. Given that both CO and NO activate guanylyl cyclase to produce cGMP and that a cGMP analog (8-Br-cGMP) showed a similar suppressive effect on the hypoxic induction of the VEGF enhancer, we speculate that the suppression of VEGF by these two gas molecules occurs via a cyclic GMP-mediated pathway.Low oxygen tension is a potent regulator of diverse biological processes, including erythropoiesis, angiogenesis, and vascular cell contractility. These effects are mediated by several proteins that are induced under hypoxic environments and modulate cell-cell interactions, cell proliferation, and differentiation. In the vasculature, hypoxia regulates the expression of genes encoding growth factors such as endothelin-1 (ET-1) 1 , platelet-derived growth factor-B (PDGF-B) and vascular endothelial growth factor (VEGF), as well as genes regulating the production of gas molecules such as nitric oxide (NO) and carbon monoxide (CO) (1)(2)(3)(4)(5). Whereas the expression of the endothelial nitric oxide synthase gene is suppressed by hypoxia, the expression of heme oxygenase-1 (HO-1), the enzyme catalyzing the production of CO, is up-regulated by hypoxia (5).Mechanisms by which hypoxia alters gene expression include transcriptional and post-transcriptional regulation (4, 6, 7). Several hypoxia-responsive cis-acting elements have been identified (8,9). We have reported the presence of a 28-bp enhancer located approximately 980 bp upstream of the VEGF transcription start site, which is necessary and sufficient to up-regulate transcription of the VEGF gene in response to hypoxia (10). This hypoxia response element contains a sequence homologous to (and now has been included into) the hypoxia-inducible factor 1 (HIF-1) consensus (11). HIF-1 is a basic helix-loop-helix transcription factor originally identified to mediate the transcriptional activation of the erythropoietin gene (8) leading to enhanced erythropoiesis under hypoxia. It was subsequently shown to regulate the expression of genes encoding glycolytic enzymes (12) and the gene for VEGF (10, 11) implicating it as an i...