No abstract

Angiogenesis, the development of new capillaries form pre-existing vessels, requires the coordinate activation of endothelial cells, which migrate and proliferate in response to growth factors to form functional vessels. Therapeutic angiogenesis is proposed to restore tissue integrity and function following damage and ischemia, while strategies aimed to block or suppress the neovascular growth are designed as adjuvant therapies for cancer treatment. Different experimental and clinical observations support the existence of a molecular/biochemical link between vasodilation, nitric oxide (NO) production and angiogenesis. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering cell growth and differentiation via endothelial-constitutive NO synthase (ecNOS) activation, and cyclic GMP (cGMP) dependent gene transcription. Re-establishment of a balanced NO production in the cardiovascular system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor growth and aggressiveness has been extensively reported in experimental and human tumors. On these bases, the nitric oxide pathway appears to be a promising target for the development of pro- and anti-angiogenic therapeutic strategies. In particular, the use of NOS inhibitors or NO scavengers seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.

No abstract

The hypothesis that thrombospondin‐1 (TSP‐1) can exert opposite effects on angiogenesis depending on the functional status of its domains/fragments was investigated. In the rabbit cornea, TSP‐1 inhibited angiogenesis induced by fibroblast growth factor‐2 (FGF‐2). However, when tested per se, TSP‐1 was able to elicit an angiogenic response comparable to that induced by FGF‐2. Induction of angiogenesis was dose‐dependent (20 ng ‐ 2 μg/pellet), was prevented by anti‐TSP antibodies or by heat‐inactivation of TSP‐1, and was not due to inflammatory mediators, to FGF‐2 or to TGF‐β. Equimolar concentrations of the 25 kDa heparin binding fragment of TSP‐1 were even more efficient than the whole molecule, and promoted the angiogenic activity of FGF‐2. On the contrary, the 140 kDa fragment of TSP‐1 did not induce angiogenesis and turned off the angiogenic response to FGF‐2. The 25 kDa fragment and TSP‐1, but not the 140 kDa fragment, increased endothelial cell invasiveness and stimulated the production and activation of matrix metalloproteinase‐2 (MMP‐2). Moreover, the 25 kDa fragment reduced the synthesis of the MMP‐2 inhibitor TIMP‐2, while the 140 kDa fragment caused a twofold increase in TIMP‐2 production and inhibited MMPs stimulation by TSP‐1 and FGF‐2. We conclude that TSP‐1 is a source of smaller mediators of angiogenesis, which affect in an opposite way endothelial cell functions and proteolytic activity, thus resulting in an opposite final effect on angiogenesis.