Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma

Abstract

Dopamine is a catecholamine that acts both as a neurotransmitter and as a hormone, exerting its functions via dopamine (DA) receptors that are present in a broad variety of organs and cells throughout the body. In the circulation, DA is primarily stored in and transported by blood platelets. Recently, the important contribution of DA in the regulation of angiogenesis has been recognized. In vitro and in vivo studies have shown that DA inhibits angiogenesis through activation of the DA receptor type 2. Overproduction of catecholamines is the biochemical hallmark of pheochromocytoma (PCC) and paraganglioma (PGL). The increased production of DA has been shown to be an independent predictor of malignancy in these tumors. The precise relationship underlying the association between DA production and PCC and PGL behavior needs further clarification. Herein, we review the biochemical and physiologic aspects of DA with a focus on its relations with VEGF and hypoxia inducible factor related angiogenesis pathways, with special emphasis on DA producing PCC and PGL.-Osinga, T. E., Links, T. P., Dullaart, R. P. F., Pacak, K., van der Horst-Schrivers, A. N. A., Kerstens, M. N., Kema, I. P. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma.

Keywords: VEGF; angiogenesis; hypoxia-inducible factor.

Figure 1.

Biosynthesis and metabolism of DA. DA is deaminated by MAO to DOPAL, which is metabolized to DOPAC by AD and to DOPET by AR. DOPET is metabolized by COMT to MOPET. DOPAC and MOPET are metabolized to HVA, the end product of DA metabolism. PAH, phenylalanine hydroxylase.

Figure 2.

Uptake and storage of DA from the extracellular milieu into the vesicle of neuronal and non-neuronal cells. The DAT transports DA into the neuronal or non-neuronal cell. In the cytoplasm, DA is taken up into storage vesicles via VMAT. It is presumed that, when DA binds to DAT, together with Na⁺ and Cl⁻, they promote a change in the conformation of DAT from a primarily outward-facing to a predominantly inward-facing transporter. In sympathetic nerves, DA can also be released by exocytosis (38).

Figure 3.

Signaling networks regulated by DA in D1-like receptors, D2-like receptors and D1-D2 receptor heteromers. DA D1-like family and D2-like family receptor homodimers signal through Gα_s/olf and Gα_i/o protein to regulate cyclic AMP through adenylyl cyclase (AC) activity. D1-like receptors activate AC through Gα_s/olf, thereby increasing intracellular cAMP and stimulating PKA. D2-like receptors inhibit AC though Gα_i/o, thereby suppressing cAMP and inhibiting PKA. The DA D1-D2 receptor heterodimer signals through Gα_q, phospholipase C, resulting in increased production of IP₃ with mobilization of intracellular calcium and of DAG with subsequent activation of PKC (41, 42).

Figure 4.

Activity of hypoxia inducible factor (HIF)-α under normoxic and hypoxic conditions. When tissue oxygen concentration is normal, HIF-α is hydroxylated by the oxygen-sensitive PHD domain proteins or FIH-1, promoting the interaction with pVHL. This process targets HIF-α for ubiquitin-mediated proteolysis, resulting in proteolytic degradation. When tissue oxygen concentration is low, the activities of PHD and FIH are reduced and degradation of HIF-α is impaired. The ensuing elevation of HIF-α levels allow the formation of an active transcription complex with HIF-β. This HIF-α/β complex binds to the HRE on the promoter region of certain genes of target cells (e.g., those encoding VEGF, VPF, and TH). In patients with a VHL gene mutation, the interaction between pVHL and hydroxylated HIF-α is disrupted, which reduces the ubiquitin-mediated proteolysis of HIF-α and causes HIF-α accumulation, which mimics a hypoxic state (–53).

Figure 5.

DA release and proposed actions of DA and VEGF in various tissues. DA and VEGF are released from activated platelets and neuroendocrine cells (NECs)/hypoxic ECs. DA can also be released by sympathetic nerves after excitation. DA inhibits the phosphorylation (i.e., activation) of the VEGF-2 receptor through activation of the D₂ receptor. As a result, proliferation and migration of EPCs and MSCs from the bone marrow are inhibited (–57).

Figure 6.

Proposed mechanism of the interplay between mitochondrial complex II and FH in the stabilization of the HIF-α signaling pathway. Mitochondrial complex II, located on the inner mitochondrial membrane, consists of SDH-proteins and catalyzes the conversion of succinate to fumarate. FH, another mitochondrial enzyme, converts succinate to malate. In the case of a mutation in one of the SDH subunits (SDHA, SDHB, SDHC, or SDHD gene mutations) or FH genes, the intracellular concentration of succinate and fumarate rise, resulting in inhibition of 2-oxyglutarate-dependent dioxygenases, including PHD, KDMs, and the TET enzymes, and leading to HIF-stimulated increase of transcription of the gene encoding TH, and to hypermethylation of the DA D₂-receptor gene (81, 83, 89, 111, 115, 160).