Multi-facets of Corticotropin-releasing Factor in Modulating Inflammation and Angiogenesis

Abstract

The family of corticotropin-releasing factor (CRF) composed of 4 ligands including CRF, urocortin (Ucn) 1, Ucn2, and Ucn3 is expressed both in the central nervous system and the periphery including the gastrointestinal tract. Two different forms of G protein coupled receptors, CRF1 and CRF2, differentially recognize CRF family members, mediating various biological functions. A large body of evidence suggests that the CRF family plays an important role in regulating inflammation and angiogenesis. Of particular interest is a contrasting role of the CRF family during inflammatory processes. The CRF family can exert both proand anti-inflammatory functions depending on the type of receptors, the tissues, and the disease phases. In addition, there has been a growing interest in a possible role of the CRF family in angiogenesis. Regulation of angiogenesis by the CRF family has been shown to modulate endogenous blood vessel formation, inflammatory neovascularization and cardiovascular function. This review outlines the effect of the CRF family and its receptors on 2 major biological events: inflammation and angiogenesis, and provides a possibility of their application for the treatment of inflammatory vascular diseases.

Keywords: Angiogenesis effect; Corticotropin-releasing factor; Inflammation; Urocortins.

Figure 1.

The corticotrophin-releasing factor (CRF) family members and their receptors. The CRF system is composed of natural ligands (CRF and urocortin [Ucn] 1–3) and 2 G-protein-coupled receptors (CRF₁ and CRF₂). CRF₁ and CRF₂ receptors exert differential binding affinity to each of the CRF family members. CRF₁ receptor binds to CRF and Ucn1, while CRF₂ receptor binds to Ucn1, Ucn2, and Ucn3.

Figure 2.

Cardiovascular function of the corticotrophin-releasing factor (CRF) family. (A) The CRF family delivered into the brain elevates blood pressure (mean arterial pressure) and heart rate, whereas systemic administration of the CRF family decreases blood pressure and heart rate. (B) A group of Ucn and its receptor CRF receptor 2 (CRF₂) have a cardioprotective effect against myocardial infarction and heart failure through the activation of extracellular signal-related kinase 1/2 (Erk1/2) pathway. In parallel, they induce vasodilation through the activation of cAMP-dependent protein kinase A (PKA) and consequent nitric oxide (NO) production.