Functional and molecular MR imaging of angiogenesis: Seeing the target, seeing it work

Intensive research over the last years led to the discovery of multiple molecular pathways and intricate regulatory network controlling the growth and regression of blood vessels in general and angiogenesis in particular. The difficulties in elucidation of the regulation of angiogenesis, stems from the inherent complexity due to participation of many cell types, under a dominant impact of physiological and environmental effects of flow, perfusion, and oxygenation. Major advances were achieved with the use of sophisticated transgenic mice models engineered so as to provide spatially and temporally controlled expression of specific factors alone or in combination. In vivo analysis of these models frequently requires the use of non-invasive imaging modalities for measurement of functional parameters of the vasculature along with dynamic molecular information. Optical methods are extensively applied for the study of angiogenesis [Brown et al,, 2001] but provide very limited tissue penetration. MRI offers the advantage of being non-invasive with uniform and relatively high spatial resolution for deep tissues. Multiple MRI approaches for monitoring angiogenesis were developed over the last years, each looking at a particular step in the process. The aim of this paper is to analyze the clinical, pharmaceutical, and biological needs for imaging of angiogenesis, and to critically evaluate the strengths and weaknesses of functional and molecular imaging for monitoring angiogenesis. The inherent problem of validation of different measures of angiogenesis, and the advantages and limitations associated with application of MRI based methods, as surrogates for other measurements of angiogenesis will be discussed. The terms molecular imaging and functional imaging are frequently loosely defined with a significant overlap between the two. For the sake of this paper we will apply a narrower definition of both terms, where molecular imaging will apply to methods directed towards detection of specific biological molecules that participate directly in (regulation of) a physiological process; while functional imaging will be used to describe those methods that aim to detect the physiological response to a defined (molecular) stimulus.