G Protein-Coupled Receptors at the Crossroad between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts

Abstract

G protein-coupled receptors (GPCRs) have been implicated in transmitting signals across the extra- and intra-cellular compartments, thus allowing environmental stimuli to elicit critical biological responses. As GPCRs can be activated by an extensive range of factors including hormones, neurotransmitters, phospholipids and other stimuli, their involvement in a plethora of physiological functions is not surprising. Aberrant GPCR signaling has been regarded as a major contributor to diverse pathologic conditions, such as inflammatory, cardiovascular and neoplastic diseases. In this regard, solid tumors have been demonstrated to activate an angiogenic program that relies on GPCR action to support cancer growth and metastatic dissemination. Therefore, the manipulation of aberrant GPCR signaling could represent a promising target in anticancer therapy. Here, we highlight the GPCR-mediated angiogenic function focusing on the molecular mechanisms and transduction effectors driving the patho-physiological vasculogenesis. Specifically, we describe evidence for the role of heptahelic receptors and associated G proteins in promoting angiogenic responses in pathologic conditions, especially tumor angiogenesis and progression. Likewise, we discuss opportunities to manipulate aberrant GPCR-mediated angiogenic signaling for therapeutic benefit using innovative GPCR-targeted and patient-tailored pharmacological strategies.

Keywords: GPCR; GPER; HIF-1; SDF-1; VEGF; sphingosine-1P; tumor angiogenesis; tumor microenvironment.

Figure 1

G-protein coupled receptors (GPCRs) classification. The International Union of Pharmacology (IUPHAR) classification (left column) applies to both vertebrates and invertebrates (Class D and E are unique to invertebrates). The GRAPH system (middle column) applies specifically to vertebrates.

Figure 2

GPCRs involved in tumor angiogenesis. GPCR signaling mediates the cross-communication between stromal, endothelial and cancer cells toward neoangiogenesis and tumor progression.

Figure 3

Schematic representation of the most relevant GPCRs, ligands, downstream pathways and candidate drugs involved in the regulation of the angiogenic process. S1P1, sphingosine 1 phosphate receptor 1; AGTR1, angiotensin II receptor type 1; GPER, G protein-estrogen receptor; EGFR, epidermal growth factor receptor; CXCR4, C-X-C chemokine receptor type 4; PAR1, protease activated receptor 1; S1P, sphingosine 1 phosphate; AngII, angiotensin II; EGFR, epidermal growth factor; CXCL12, C-X-C motif chemokine 12; GTP, guanosine triphosphate; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; HIF-1α, hypoxia inducible factor-1 α; STAT, signal transducer and activator of transcription; FAK, focal adhesion kinase; EGR-1, early growth response protein 1; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; DAG, diacylglycerol; MMP, matrix metalloproteinase; CDC42, cell division cycle 42; PAK, p21 activated kinase; RAC, ras-related c3 botulinum toxin substrate 1.