The sticky truth about angiogenesis and thrombospondins

Abstract

The formation of new blood vessels, a process known as angiogenesis, is important for embryonic development and wound healing as well as the development of cancer and inflammation; therefore, angiogenesis is a valuable target for clinical intervention. Both logic and empiricism suggest that a balance of stimulatory and inhibitory switches is required for orderly formation of blood vessels. Thrombospondins 1 and 2 were among the first natural angiogenesis inhibitors to be identified. However, the cellular origins and mechanisms of action of these important proteins during angiogenesis have remained largely unknown. Studies by Kopp et al., presented in this issue of the JCI, clarify some of these issues by revealing that megakaryocytes and their "sticky" wound-healing progeny, platelets, are important sources of thrombospondins 1 and 2 and that these thrombopoietic cells play key roles in controlling blood vessel formation during hematopoiesis and ischemic wound healing (see the related article beginning on page 3277).

Figure 1. TSPs released by thrombopoietic cells during wound healing act as angiogenic switches and control the extent of revascularization.

Megakaryocytes in the bone marrow give rise to platelets that carry large stores of TSPs in their α-granules. Circulating platelets traffic from bone marrow to sites of injury and, for example, adhere to components of the blood vessel wall in order to plug gaps in wounded blood vessels. Simultaneously these platelets release pro-angiogenic growth factors, such as VEGF, MMP-9, and SDF-1. In this issue of the JCI, Kopp et al. (5) show that TSPs released by megakaryocytes and platelets have an antiangiogenic effect. The TSPs act as an angiogenic “switch,” binding to MMP-9 and SDF-1 to inhibit the angiogenic cascade and limit the extent of vascularization. The signals that control the balance and timing of the release of pro- and antiangiogenic factors in tissues have yet to be fully determined. The authors also show that TSP1 and TSP2 negatively regulate megakaryocyte proliferation in the bone marrow and consequently regulate platelet numbers in the blood.