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Tip cell (green) filopodia follow VEGF-A–expressing astrocytes (red).

On page 1163, Gerhardt et al. present a mechanism to explain the function of VEGF in angiogenesis. Their findings implicate a specialized cell at the tips of vessels in guiding the growth of new sprouts, with cell mass provided by the division of different cells that lie further back.

The authors examined angiogenesis in mice retina. Retinal vessels grow by circular expansion and are thus convenient for examining newly sprouting vessels. Past images have suggested that the ends of growing vessels harbor an unusual tip structure. In this article, the authors show that this highly polarized tip cell is specialized to respond uniquely to VEGF-A isoforms. Tip cells extended long filopodia that followed along tracks of astrocyte cells. The filopodia used the VEGFR2 receptor to sense a gradient of VEGF-A, which is secreted by the astrocytes and thus guides the tip cells' migration. Loss of the gradient, as found in knock-out mice that have only a uniformly expressed VEGF-A isoform, disturbed filopodial polarity. Misexpression of VEGF-A caused ectopic filopodial sprouting in transgenic mice.

Stalk cells (those growing behind the tip cells) also responded to VEGF-A isoforms. However, stalk cells were responsive to absolute concentrations of the growth factor, not gradients, and reacted by proliferating. In contrast, tip cells were nonproliferative and appear specialized for guidance and migration. The filopodia also express integrins, which could help to pull the cells along the matrix, perhaps by binding fibronectin, which is deposited by astrocytes. The authors have found similar tip cells throughout the developing central nervous system. Tumor vessels also have tip cells, but show signs of filopodial misguidance resembling transgenic mice overexpressing VEGF. That a specific pattern of VEGF deposition is required for vessel growth will present a challenge for those attempting to elicit angiogenesis for therapeutic purposes. ▪