Hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis, which is disrupted in disorders affecting the circulatory system and in cancer. The role of HIFs in these diseases has been elucidated by clinical studies and by analyses of mouse models. HIFs play a protective role in the pathophysiology of myocardial ischemia due to coronary artery disease, limb ischemia due to peripheral arterial disease, pressure-overload heart failure, wound healing, and chronic rejection of organ transplants. In contrast, HIFs contribute to the pathogenesis of pulmonary arterial hypertension, systemic hypertension associated with sleep apnea, ocular neovascularization, hereditary erythrocytosis, and cancer.

Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology

Objective
Macrophages show extreme heterogeneity and different subsets have been characterized by their activation route and their function. For instance, macrophage subsets are distinct by acting differently under pathophysiological conditions such as inflammation and cancer. Macrophages also contribute to angiogenesis, but the role of various specific subsets in angiogenesis has not been thoroughly investigated.

Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo

At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-α and related family members leading to activation of NF-κB; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

Molecular Biology of Atherosclerosis

The clinical complications of atherosclerosis are caused by thrombus formation, which in turn results from rupture of an unstable atherosclerotic plaque. The formation of microvessels (angiogenesis) in an atherosclerotic plaque contributes to the development of plaques, increasing the risk of rupture. Microvessel content increases with human plaque progression and is likely stimulated by plaque hypoxia, reactive oxygen species and hypoxia-inducible factor (HIF) signalling. The presence of plaque hypoxia is primarily determined by plaque inflammation (increasing oxygen demand), while the contribution of plaque thickness (reducing oxygen supply) seems to be minor. Inflammation and hypoxia are almost interchangeable and both stimuli may initiate HIF-driven angiogenesis in atherosclerosis. Despite the scarcity of microvessels in animal models, atherogenesis is not limited in these models. This suggests that abundant plaque angiogenesis is not a requirement for atherogenesis and may be a physiological response to the pathophysiological state of the arterial wall. However, the destruction of the integrity of microvessel endothelium likely leads to intraplaque haemorrhage and plaques at increased risk for rupture. Although a causal relation between the compromised microvessel structure and atherogenesis or between angiogenic stimuli and plaque angiogenesis remains tentative, both plaque angiogenesis and plaque hypoxia represent novel targets for non-invasive imaging of plaques at risk for rupture, potentially permitting early diagnosis and/or risk prediction of patients with atherosclerosis in the near future.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.2518

Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis

Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions: relevance of compromised structural integrity for intraplaque microvascular leakage

Job L. van Wanroij

Papers

Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis.