Jeffrey M. Isner, and Takayuki Asahara

Departments of Medicine (Cardiology) and Biomedical Research, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA.

Received 4/6/98 Accepted 4/29/98

4. PERSPECTIVES

The identification of angiogenic growth factors has generated the opportunity for novel therapies in the treatment of a variety of diseases. This includes pathologic angiogenesis, such as diabetic retinopathy, rheumatoid arthritis, and cancer. In these cases, antibodies and/or naturally occuring angiogenesis inhibitors are being investigated clinically to antagonize key angiogenic factors. The strategy is designed to eliminate the vascular infrastructure and thereby minimize the extent of pathological consequences to the patient.

A complementary strategy is likely to emerge for the treatment of cardiovascular diseases. Clinical trials of therapeutic angiogenesis have already been initiated in patients with myocardial ischemia and peripheral vascular disease. These include trials of recombinant protein therapy as well as gene transfer. While preliminary applications of gene therapy have established proof of concept that angiogenic growth factors can augment collateral artery development in human subjects, many questions remain to be answered. What are the relative advantages of protein versus gene therapy, both in terms of bioactivity as well as cost and safety? What is the maximum extent of clinical improvement that can be expected? How is the therapeutic outcome affected by certain features of the host?

It is also likely that future investigations may clarify the impact on established risk factors for vascular disease, such as lipid dyscrasias and diabetes, on native angiogenesis; thus risk factor modifications may be useful for indirectly aiding natural angiogenesis in ischemic territories. It is intriguing to consider the possibility that one may be able to identify certain genotypic characteristics that may indicate why some patients from robust collateral networks, while others fail to do so.

The role of endothelial cell (EC)progenitors in both natural as well as therapeutic angiognesis will be clarified by future studies. Recent studies have forced us to modify the classic concept that collateral development occurs solely by migration of fully differentiated ECs. It is now clear that circulating stem cells contribute to such neovascularization. What remains to be determined is the proportion of new vessel growth that results from circulating stem cells versus parent vessel ECs. Finally, it is possible that EC progenitors may be employed in strategies of "supply side" therapuetic angiogenesis; specifically can administration of EC progenitors, including cells engineered to secrete pro-angiogenic agents, complement the impact of angiogenic cytokines on collateral vessel growth?