Pro-angiogenic Role of Insulin: From Physiology to Pathology

Abstract

The underlying molecular mechanisms involve in the regulation of the angiogenic process by insulin are not well understood. In this review article, we aim to describe the role of insulin and insulin receptor activation on the control of angiogenesis and how these mechanisms can be deregulated in human diseases. Functional expression of insulin receptors and their signaling pathways has been described on endothelial cells and pericytes, both of the main cells involved in vessel formation and maturation. Consequently, insulin has been shown to regulate endothelial cell migration, proliferation, and in vitro tubular structure formation through binding to its receptors and activation of intracellular phosphorylation cascades. Furthermore, insulin-mediated pro-angiogenic state is potentiated by generation of vascular growth factors, such as the vascular endothelial growth factor, produced by endothelial cells. Additionally, diseases such as insulin resistance, obesity, diabetes, and cancer may be associated with the deregulation of insulin-mediated angiogenesis. Despite this knowledge, the underlying molecular mechanisms need to be elucidated in order to provide new insights into the role of insulin on angiogenesis.

Keywords: angiogenesis; endothelial cells; insulin; insulin receptor.

Figure 1

Role of “tip” and “stack” cells on angiogenesis process. (A) Release of angiogenic factors (which include VEGF, ANG-2, FGF, chemokines, inflammatory, and tumor mediators) from hypoxic area (B). Activation of endothelial cells in the microcirculation. Mural cells in the vascular wall (i.e., pericytes) are detached, while basement membrane is degraded. Protein exudates form a provisional extracellular matrix scaffold where (C). Tip endothelial cells start to migrate. Meanwhile, neighbor endothelial cells form “stack cells.” (D) Formation of nascent new blood vessel. (E) Formation of functional vessel as a stable tube in which permanent blood flow is passing through.

Figure 2

Insulin-mediated pericyte and endothelial cell-to-cell interaction during angiogenesis. As described in this manuscript, few reports have analyzed the potential role of insulin in the endothelial-pericyte interactions during cell proliferation/migration or vessel maturation. The molecular mechanisms summarized in this schematic representation indicate that on endothelial cells, insulin, either directly or via vascular endothelial growth factor (VEGF) expression, is involved in promoting angiogenesis. Insulin also activates insulin receptors present on pericytes leading to survival and proliferation of these cells. In pericytes, insulin induces expression of VEGF, which might reach its respective receptors on the endothelial cell surface and control endothelial survival. Alternatively, insulin can activate mobilization of progenitor cells (PC), which might differentiate into either pericytes or endothelial cells. Until now it is unknown whether insulin uses transcellular or paracellular transport mechanisms in endothelial cells to reach the subendothelial space and then activate insulin receptors on pericytes.

Figure 3

Summary of insulin actions in angiogenesis. Insulin receptor activation leads to endothelial cell survival, differentiation and growth via activation of MAPKs. Additionally, insulin receptor activation leads to nitric oxide (NO) synthesis via PI3K-AKT activation, which in turn regulates endothelial survival, migration, proliferation, and vascular permeability. Additionally, NO may regulate the expression of vascular endothelial growth factor (VEGF), but the molecular mechanisms that underlie this effect are still unclear. Alternatively, insulin mediates a pro-angiogenic effect by expression and secretion of VEGF, which then can activate VEGF receptors (mainly VEGFR2), leading to activation of phosphorylation cascades including cross-talk (dashed lines) between insulin-mediated PI3K and endothelial nitric oxide synthase (eNOS) or by directly activating MAPKs generation of pro-angiogenic effects on endothelial cells.