Effects of Inhibition of Lung Overexpression of Angiostatin on Development of Experimental Pulmonary Hypertension in Mice

As mentioned earlier, the physiological or pathological consequences of hypoxia-induced activation of lung angiogenic processes are not completely understood. Pharmacological blockade of VEGF receptors aggravates [32]

whereas lung VEGF overexpression by adenovirus mediated gene transfer attenuates development of hypoxic pulmonary hypertension [28]. However, VEGF is only one among various angiogenic molecules that are upregu-lated during chronic hypoxia. Moreover, VEGF receptors are present not only on endothelial cells but also on lung epithelial cells and monocytes [2,4]. Finally, the regulation of angiogenesis is a complex process, which depends upon the local balance between proangiogenic and antiangiogenic molecules. In recent studies, we questioned whether changing the angiogenic set point by inducing lung overexpression of an endogenous angiogenesis inhibitor would alter development of hypoxic pulmonary hypertension. Indeed, physiological angiogenesis is a highly regulated process under the control of both angiogenic and antiangiogenic factors. A number of endogenous angiogenesis inhibitors have been identified that antagonize the effects of VEGF, FGFs and other angiogenic factors. Among those is angiostatin, a 38-kDa fragment of plasminogen, which has been shown in vitro to inhibit endothelial cell proliferation and in vivo to exhibit potent antitumor and antiangiogenic properties [25]. Although the mechanism of its action is not completely understood, numerous studies indicate that angi-ostatin is a highly specific angiogenesis inhibitor [6,5].

In these studies, angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule driven by the cytomegalovirus promoter (Ad.K3) [29]. We first evaluated the efficiency of gene transfer in the lungs from mice with a single intratracheal instillation of the adenovirus by detecting the protein in bronchoalveolar lavage (BAL) fluid. We found that adenoviral-mediated lung overexpression of the angio-genesis inhibitor, angiostatin, aggravated development of hypoxic pulmonary hypertension in mice. Evidence for an activation of endogenous angiogenic processes in the lung during exposure to hypoxia was highly suggested by the observation that factor VIII endothelial cell immunostaining was increased in chronically hypoxic mice (Figure 2). This change was suppressed by pre-treatment with Ad-angiostatin, which also inhibited in vitro endothelial cell growth and migration [29]. Since treatment with Ad-angiostatin did not affect PA-SMCs function in vitro, but potentiated pulmonary hypertension and aggravated structural vascular remodeling in chronically hypoxic mice, the results indicate that counteracting lung angiogenic processes aggravates development of hypoxic pulmonary hypertension.

These results differ to some extent from those obtained by Taraseviciene-Stewart et al. [32]. In this study, treatment of rats with SU5416, a selective VEGF receptor tyrosine kinase inhibitor caused mild pulmonary hypertension and pulmonary vascular remodeling in normoxic rats and severe, irreversible pulmonary hypertension associated with some endothe-lial cell proliferation in chronically hypoxic rats [32]. It is not clear why

Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook

Post a comment