Interpreting the Conflicting Data

It is difficult to reconcile the conflicting experimental data regarding the necessity of avp3 function during pathological, and especially tumor, neovascularization. It is important to note that the antagonism of an existing integrin function is certainly quite different from ablation of the inte-grin gene product. Thus, one should exercise caution when interpreting data using such different experimental approaches. However, there are cases where genetic ablation of integrin expression and acute inhibition of integrin function lead to quite similar results. For example, various data using b3 antagonists implicate avp3 as important for bone reabsorption. This function is also revealed after ablation of the b3 gene. Antibody or peptide inhibition of the platelet integrin aIIbp3 leads to defective platelet aggregation. Mutations in the human p3 gene also lead to abnormal platelet aggregation and the bleeding disorder Glanzmann thrombasthenia. p3-null mice develop abnormalities that are very similar to this human disease. Similarly, genetic ablation of the a5 gene, as well as acute inhibition of a5 function, both clearly show that this integrin is important for neovascularization.

Accumulating data support the concept of cross-talk pathways existing among different integrins. Inhibition of one integrin signaling cascade can in turn affect other inte-grin-mediated signaling events. Thus, antagonists that perturb avb3 function may be affecting other integrins involved in neovascularization, possibly including a5pi and/or aipi. Another likely possibility, discussed in more detail later, is that in some cases a given integrin can be pro-or antiangiogenic. For example, growing evidence suggests that avp3 is a negative regulator of pathological angiogenesis. Ablation of the p3 gene would remove this negative regulation, leading to enhanced neovascularization. This is indeed the result during pathological angiogenesis in the p3-null mouse model. In any case, it is likely that the acute inhibitors of angiogenesis are affecting microvascular events in a far more complicated manner than originally expected, and more extensive reviews discussing these possibilities have recently been published [5, 7].

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Essentials of Human Physiology

Essentials of Human Physiology

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