Hypoxia-induced increase of endostatin in murine aorta and lung

Abstract

In the lung, hypoxia induces pulmonary hypertension caused by vasoconstriction and vascular remodeling. Additionally, hypoxia is an inducer of angiogenesis, which is assumed to counteract pulmonary hypertension. We asked whether the anti-angiogenic factor endostatin--a cleavage product of collagen XVIII--participates in the vascular alterations induced by hypoxia. By employing Western blotting of tissue extracts of murine brain, liver and heart an endostatin fragment of 22 kDa was detectable, whereas in lung and aorta additional bands of 24 and 26 kDa were found. The amount of these larger fragments was increased in tissues obtained from mice housed for 4 days or 3 weeks at hypobaric hypoxia. By immunohistochemistry endostatin was detected in association with elastic fibers and in close neighborhood to smooth muscle cells of intrapulmonary vessels and the aorta. In the lung, the activity of matrix metalloproteinases (MMP) known to generate endostatin by cleavage of collagen XVIII was increased (MMP-2) and decreased (proMMP-9), respectively, by hypoxia. Elevated amounts of endostatin within the aortic wall of mice exposed to hypobaric hypoxia may stabilize the vascular wall by inhibition of microvascular sprouting. The surprising finding of increased endostatin in the lung presumably contributes to the development of pulmonary hypertension by reduction of angiogenesis.

Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas

“…This absence of angiogenesis is at variance with the expected findings, in light of the high levels of vascular endothelial growth factor in bronchoalveolar lavage fluids reported in sarcoidosis, and in epithelioid cells detected by immunohistochemistry and in situ hybridisation [21,22]. Conversely, macrophages are also known to secrete anti-angiogenic factors, such as endostatin/ collagen XVIII [23]. However, the secretion of such factors by epithelioid or giant cells has not been reported.…”

Hypoxia-Regulated Pro- and Anti-Angiogenesis in the Heart

“…Hypoxia-induced endostatin inhibits VEGF-induced angiogenesis by preventing proliferation and migration of endothelial cells (Abdollahi et al, 2004;Heljasvaara et al, 2005;Morbidelli et al, 2003) and simultaneously up-regulates anti-angiogenic genes, including thrombospondin (TSP1), vasostatin, and kininogen (Abdollahi et al, 2004). Reduced oxygen supply in FVB mice exposed to a hypobaric hypoxia chamber showed enhanced MMP production leading to a subsequent increase of endostatin generation in the lung and aorta (Paddenberg et al, 2006). These results were confirmed by Suhr et.…”

Diminished Pulmonary Expression of Hypoxia-Inducible Factor 2-<I>α</I>, Vascular Endothelial Growth Factor and Hepatocyte Growth Factor in Chickens Exposed to Chronic Hypobaric Hypoxia

“…Anti-angiogenic agents (Paddenberg et al, 2006), the possible role of oxidative stress (Cawthon et al, 2001;Iqbal et al, 2001a, b;Paternotte et al, 2008) and changes in the vesicle trafficking system (Mukhopadhyay et al, 2007;Patel et al, 2007) are topics which might be useful to analyze as to establish their potential role on gene transcription, cell signaling and pulmonary angiogenesis. Endogenous antiangiogenic agents such as endostatin can be increased in response to oxidative stress (Deininger et al, 2003) and its presence is enhanced in the lungs of mice exposed to chronic hypobaric hypoxia (Paddenberg et al, 2006). Additionally, endostatin has the capability to diminish mRNA expression of genes HIF-1α, VEGF, VEGFR2, HGF, EGFR, included in this report, and increase the mRNA expression of thrombospondin, another antiangiogenic agent (Abdollahi et al, 2004).…”