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Focal adhesion kinase and angiogenesis. Where do we go from here?

Maria Teresa Rizzo
DOI: http://dx.doi.org/10.1016/j.cardiores.2004.09.011 377-378 First published online: 1 December 2004

See article by Peng et al. (pages 421–430) in this issue.

Processes involved in the generation of new blood vessels during embryonic development, wound healing, ischemia, inflammation and tumor growth have captured the imagination of investigators for many years. Numerous studies have led to the well-founded expectation that regulation of angiogenesis will soon be a therapeutically useful approach for a wide range of disorders, ranging from inflammation to neoplastic growth [1]. The angiogenic response is a multifaceted and highly orchestrated process initiated by the endothelial cells of preexisting capillaries. [2]. Responding to a wide array of external stimuli, endothelial cells engage in a series of events that lead to degradation of the extracellular matrix, apparently allowing the cells to proliferate, migrate freely into the perivascular space and differentiate into capillary-like structures [2,3]. The subsequent integration of mural cells and other perivascular cells on the surface of the developing endothelium results in the transformation of these immature tube-like structures into functionally mature blood vessels [2,4]. During neovascularization, the importance of the relationship of the endothelial cells with the microenvironment cannot be overemphasized [5]. In fact, the ability of the endothelial cells to adequately respond to angiogenic challenges is highly dependent on both their interactions with the extracellular matrix and agonists [5,6]. Adhesion of cells to the extracellular matrix optimally promotes migration and other cellular processes at the specific stages of the angiogenic response [5,7]. Conversely, failure of endothelial cells to appropriately adhere to the extracellular matrix rapidly leads to their demise [5–8]. On the other hand, strong adherence of the endothelial cells to the extracellular matrix can paralyze cells, holding them in place and keeping them away from the area of neovascularization [5–8]. Adding to the dynamics of the angiogenic response are changes in the composition of the extracellular matrix near sites of injury, infection, ischemia and tumor growth [5]. How the interactions of the endothelial cells with a continuously changing microenvironment integrate into an efficient response that results in neovascularization is not understood, but several studies have led to the identification of key mediators involved in this highly orchestrated and complex response [2,5]. The study by Peng et al. [9] published in this issue of Cardiovascular Research provides evidence that the focal adhesion kinase (FAK), a key mediator of endothelial cell–matrix interactions [10], acts to optimize angiogenesis in vivo.

FAK, a non-receptor tyrosine kinase localized to focal adhesions, plays a crucial role in linking signals initiated by the integrins or growth factor receptors to intracellular cytoskeletal and signaling proteins, thus controlling essential cellular processes such as growth, survival, migration and differentiation [10]. Upon integrin-mediated cell adhesion, or growth factor receptor stimulation, FAK is rapidly phosphorylated at Tyr397 [10]. This creates a high-affinity binding site for signaling molecules carrying SH2 domains, including the Src family protein kinases. Recruitment of Src and other signaling partners leads to phosphorylation of additional tyrosine residues within the kinase and C-terminal domains of FAK, resulting in its full activation [10]. Work from several laboratories points to the importance of FAK in influencing distinct steps of the angiogenic response and suggests a critical role of FAK in angiogenesis. For example, FAK stimulates the secretion of metalloproteinases, thus facilitating the movement of endothelial cells through the membrane basement into the interstitial space [11]. Moreover, recent studies demonstrate that growth factor-induced migration of endothelial cells is dependent on FAK, similar to earlier findings demonstrating that FAK-deficient fibroblasts migrated poorly to chemotactic or haptotactic stimuli [12,13]. Additionally, recent studies demonstrate that FAK is involved in morphogenic differentiation of brain endothelial cells [14]. While these findings implicate FAK in the regulation of angiogenesis in vitro, the in vivo data to reinforce such a possibility are limited. In the chick chorioallantoic membrane (CAM) assay, an in vivo assay for angiogenesis, a retrovirus encoding the noncatalytic COOH-terminal domain of FAK, known as FRNK, which interferes with FAK localization to the focal adhesions, inhibited blood vessel growth induced by bFGF [15]. Furthermore, high levels of FAK and FAK phosphorylated at Tyr397 were detected in microvascular endothelial cells of malignant astrocytoma biopsy samples, but not in endothelial cells of normal brain [14]. Clearly, more studies are needed to examine the contribution of FAK to neovascularization in vivo.

The study by Peng et al. [9] represents an important step toward this direction. Using an elegant genetic approach that allows the targeting of heterologous genes exclusively to endothelial cells in vivo, the authors generated transgenic mice overexpressing chicken FAK cDNA under the control of the Tie-2 promoter. Expression of the ectopic FAK was monitored in isolated endothelial cells using a species-specific antibody. The authors employed two well-established models of in vivo angiogenesis, the wound healing and hind limb ischemia assays, to address the contribution of FAK overexpression to neovascularization. Enhanced vascularity was consistently detected in the wounded skin of the transgenic mice compared to the wild-type animals. Importantly, this increase was confined to the injury site. Transgenic animals displayed a similar increase of vascular density at the sites of ischemic injury, but not in the non-ischemic hind limb. The increased microvessel density correlated with the degree of FAK overexpression, suggesting that neovascularization detected in the areas of wound injury or ischemia is dependent upon FAK upregulation. Furthermore, the lack of increased neovascularization in the normal skin or muscles suggests that FAK overexpression in the endothelial cells enhances their responsiveness to subsequent angiogenic challenges. The animal model developed by Peng et al. further provides a valuable tool for future studies aimed at elucidating additional aspects of the role of FAK in angiogenesis in vivo. The involvement of FAK in other in vivo settings of angiogenesis can be studied and compared to elucidate potential differences in the role of FAK in neovascularization under different physiopathological conditions. Furthermore, the spatial and temporal activation of FAK and whether FAK signals to different downstream pathways, depending on the microenvironmental conditions under which the angiogenic response occurs, can be examined and dissected in vivo. In conclusion, the work of Peng and colleagues provides a solid rationale for further studies as it compellingly shows that FAK indeed plays an important role in angiogenesis in vivo. How it does so remains to be defined, but the answer to this question will provide a rational basis for the development of newer and more efficient strategies to facilitate the manipulation of angiogenesis for therapeutic purposes.

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