The Multifaceted Role of Mitochondria in Angiogenesis

Abstract

Angiogenesis, the formation of new blood vessels from pre-existing ones, is crucial for various physiological and pathological conditions, including embryonic development, wound healing, tissue regeneration and tumor progression. While traditionally attributed to the actions of growth factors and their receptors, emerging evidence highlights the crucial regulatory roles of mitochondria in angiogenesis. This narrative review explores the multifaceted functions of mitochondria in endothelial cells, which are central to blood vessel formation. Beyond their classical role in ATP production, mitochondria contribute to angiogenesis through redox signaling, calcium homeostasis, biosynthetic activity, and reactive oxygen species (ROS) generation. These organelles help regulate key endothelial behaviors such as proliferation, migration, and tube formation through mechanisms that include mitochondrial calcium signaling and ROS-mediated stabilization of hypoxia-inducible factor-1α (HIF-1α), leading to increased vascular endothelial growth factor (VEGF) expression. Additionally, mitochondrial dynamics, dysfunction, and genetic factors are discussed for their influence on angiogenic outcomes. Understanding these complex mitochondrial functions opens new therapeutic avenues for modulating angiogenesis in diseases such as cancer and cardiovascular disorders.

Keywords: VEGFR2; angiogenesis; mitochondria; mitochondrial calcium transport; mtROS-HIF1a-VEGF axis.

Figure 1

Mechanisms of ischemia and tumor blood vessel formation. Shared mechanisms: (a) Sprouting angiogenesis—new vessels from existing ones; (b) Intussusceptive angiogenesis—vessel lumen splits into two; (c) Vasculogenesis—bone marrow-derived EPCs differentiate into ECs to form vessels. Tumor-specific mechanisms: (d) Vascular mimicry—tumor cells form vessel-like structures; (e) Vessel co-option—tumors hijack existing vessels; (f) CSC trans-differentiation—cancer stem cells become ECs to support vasculature. As a result, tumor blood vessels are typically chaotic, twisted, and leaky. In contrast (g) ischemic angiogenesis produces new blood vessels well-organized, stable, and functionally mature, designed to restore proper blood flow to the affected tissue.

Figure 2

The Angiogenic Switch in Pathological Conditions. In pathological settings such as cancer, a tightly regulated balance between pro- and anti-angiogenic factors is disrupted, leading to the activation of the “angiogenic switch.” This process is characterized by metabolic reprogramming in endothelial cells, including increased glucose uptake and enhanced glycolysis, which fuel rapid proliferation and support the formation of new vasculatures. Tumors exploit this switch to promote neovascularization and sustain growth. Key anti-angiogenic factors include the tissue inhibitor of metalloproteinases-2 (TIMP2) and endostatin, whereas pro-angiogenic signals are driven by matrix metalloproteinases (MMPs) and the vascular endothelial growth factor and its receptor (VEGF/VEGFR).

Figure 3

The mtROS–HIF-1α–VEGF Axis in Hypoxia-Induced Angiogenesis. Under hypoxic conditions, mitochondrial Complex III generates mitochondrial reactive oxygen species (mtROS), which diffuse into the cytosol and inhibit prolyl hydroxylase domain (PHD) enzymes. This inhibition stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), preventing its degradation. Stabilized HIF-1α translocates to the nucleus, promoting transcription of the vascular endothelial growth factor (VEGF). The VEGF then binds to its receptor, VEGFR2, on both mature endothelial cells and circulating endothelial progenitors (CEPs), activating downstream signaling pathways such as ERK and Akt. This leads to endothelial cell proliferation, migration, and mobilization, key steps in angiogenesis.

Figure 4

Mitochondrial Calcium Transport and Microdomain Signaling. Calcium transport into mitochondria begins at the outer mitochondrial membrane (OMM), where voltage-dependent anion channels (VDACs) mediate the flux of calcium ions from the cytosol into the intermembrane space (IMS). Calcium then traverses the inner mitochondrial membrane (IMM) via the mitochondrial calcium uniporter complex (MCU), reaching the mitochondrial matrix. Calcium efflux mechanisms include the mitochondrial Na⁺/Ca²⁺ exchanger (NCX3) and the mitochondrial permeability transition pore (mPTP). Mitochondria form specialized high calcium microdomains at contact sites with the endoplasmic reticulum (ER) and the plasma membrane (PM). These regions exhibit elevated calcium concentrations due to localized calcium entry, often facilitated by voltage-dependent calcium channels (VDCCs) at the PM, enabling efficient calcium signaling and homeostasis within the cell.

Figure 5

MitoQ and UQCRB antioxidant action. (a) MitoQ, a mitochondria-targeted CoQ10 derivative, acts as a potent antioxidant that preserves mitochondrial function and reduces oxidative stress. By limiting ROS production, it may help maintain nitric oxide signaling, prevent endothelial dysfunction, and lower cardiovascular disease (CVD) risk, which is driven by oxidative stress, inflammation, and vascular abnormalities; (b) UQCRB acts as a mitochondrial oxygen sensor in Complex III. Terpestacin inhibits hypoxic signaling by targeting UQCRB, reducing ROS production, HIF-1α stabilization, and VEGF expression, thereby suppressing tumor angiogenesis.