Lung Vegf Expression During Pulmonary Hypertension Or During Exposure To Chronic Hypoxia

Vascular endothelial growth factor (VEGF) was first described as a potent and specific mitogen for endothelial cells and a vascular permeability factor [13]. It was then found to play an important role in normal as well as pathological ang-iogenesis. VEGF is a homodimeric 34- to 42-kDa heparin-binding glycoprotein, that fulfils its function on endothelial cells by binding to flt-1 and KDR/flk-1, two highly specific tyrosine kinase receptors expressed almost exclusively on endothelial cells [13]. Evidence has been provided that stimulation of angiogen-esis under hypoxic and ischemic conditions involves upregulation of VEGF and its receptors. A unique feature of VEGF is its sensitivity to hypoxia [19]. Hypoxia is a strong inducer of VEGF expression in vitro [20]. The mechanism of hypoxic induction of VEGF expression has been partially elucidated. Hypoxia activates a specific transcription factor (Hypoxia Inducible Factor) that binds to identified hypoxia-sensitive elements in the promoter of the VEGF gene. Hypoxia may also increase VEGF expression by stabilizing VEGF mRNAs [20].

In recent studies, we examined the effects of exposure to chronic hypoxia (CH) and treatment with monocrotaline (MCT) on VEGF gene expression in heart and lung tissues of rats (Figure 1). The main finding of our study is that an angiogenic process is associated with right ventricular hypertrophy in hypoxia-induced pulmonary hypertension and that this process may be related to upregulation of VEGF expression in right ventricular tissue [27]. In contrast, monocrotaline-induced pulmonary hypertension caused right ventricular hypertrophy without cardiac angiogenesis, a finding consistent with down-regulation of VEGF gene expression in the right ventricular myocardium [27]. Taken together, these findings strongly suggest that VEGF plays an important role in controlling right ventricular perfusion during hypertrophy secondary to pulmonary hypertension. Moreover, lung VEGF mRNA levels were also strikingly decreased in rats given MCT, but remained unchanged after exposure to hypoxia. Since muscularization in distal vessels was also more marked in MCT than in hypoxic rats, it can be speculated that alterations in lung VEGF expression also affected pulmonary vascular remodeling.

Other studies have reported increased VEGF expression in lungs from rats exposed to chronic hypoxia [33,7]. Moreover, labeling studies in rats have suggested a burst of endothelial cell multiplication in intraacinar arteries at the end of the first week of exposure to hypoxia. In recent studies performed

Figure 1. Lung angiograms illustrating changes in lung vascular density in rats exposed to normoxia (control), hypoxia (hypoxia) or treated with monocrotaline (monocrotaline). Lung VEGF expression is increased in lungs from animals exposed to hypoxia but decreased in animals treated with monocrotaline (Partovian C et al.).

Figure 1. Lung angiograms illustrating changes in lung vascular density in rats exposed to normoxia (control), hypoxia (hypoxia) or treated with monocrotaline (monocrotaline). Lung VEGF expression is increased in lungs from animals exposed to hypoxia but decreased in animals treated with monocrotaline (Partovian C et al.).

in our laboratory, lung density of factor VIII immunostaining was increased in mice exposed to chronic hypoxia [29]. These results suggest that activation of lung angiogenic processes in response to hypoxia is associated with an increased number of peripheral pulmonary vessels.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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