Vasotrophic regulation of age-dependent hypoxic cerebrovascular remodeling

Abstract

Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. Better understanding of age-dependent hypoxic macrovascular remodeling processes of the cerebral vasculature and its clinical implications require knowledge of the vasotrophic factors that influence arterial structure and function. Hypoxia can affect the expression of transcription factors, classical receptor tyrosine kinase factors, non-classical G-protein coupled factors, catecholamines, and purines. Hypoxia's remodeling effects can be mediated by Hypoxia Inducible Factor (HIF) upregulation in most vascular beds, but alterations in the expression of growth factors can also be independent of HIF. PPARγ is another transcription factor involved in hypoxic remodeling. Expression of classical receptor tyrosine kinase ligands, including vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor and angiopoietins, can be altered by hypoxia which can act simultaneously to affect remodeling. Tyrosine kinase-independent factors, such as transforming growth factor, nitric oxide, endothelin, angiotensin II, catecholamines, and purines also participate in the remodeling process. This adaptation to hypoxic stress can fundamentally change with age, resulting in different responses between fetuses and adults. Overall, these mechanisms integrate to assure that blood flow and metabolic demand are closely matched in all vascular beds and emphasize the view that the vascular wall is a highly dynamic and heterogeneous tissue with multiple cell types undergoing regular phenotypic transformation.

Fig. 1. Categories of Vascular Remodeling

Remodeling can be hypertrophic, eutrophic, or hypotrophic. In hypertrophic remodeling, the medial cross-sectional area increases. In eutrophic remodeling, total medial cross-sectional area remains unchanged. In hypotrophic remodeling, cross-sectional area decreases. Remodeling that results in a reduction in luminal diameter with constant outside diameter is classified as inward remodeling (left panel). Remodeling that involves an increase in outside arterial diameter with a constant inside diameter is classified as outward remodeling (right panel). In eutrophic remodeling, both inside and outside diameters change. In the above panels, eutrophic remodeling is represented as a change in horizontal position with no vertical change. These combined structural changes profoundly influence the contractile characteristics of the individual smooth muscle cells within the medial layer.

Fig. 2. Hypoxia and Transcription Factors

Prolyl hydroxylase, the oxygen sensor, is responsible for HIF-1α ubiquitination and degradation under normoxic conditions. Hypoxia inhibits prolyl hydroxylase, leading to elevated levels of HIF-1. Accumulated HIF-1α can then facilitate the formation of the HIF-1 complex with constitutively expressed HIF-1β, which can then translocate to the nucleus where it binds to Hypoxia Responsive Elements (HRE) in the promoter regions of multiple genes and initiates transcription. Hypoxia-induced increases in TGF-β lead to Smad phosphorylation, which can also serve as coactivators for HIF-1α, and decrease PPARγ expression.

Fig. 3. Effects of Hypoxia on Expression of Receptor Tyrosine Kinase-dependent Vasotrophic Factors

Hypoxia-induced increases in HIF-1 levels can stimulate the transcription and translation of multiple Receptor Tyrosine Kinase-dependent vasotrophic factors. HIF-induced increases in FGF have been shown to stabilize HIF-1α, effectively enhancing its own synthesis. Increases in VEGF and VEGF receptors can induce endothelial cell proliferation. In addition to having angiogenic effects, VEGF can also be neuroprotective, can induce endothelial cell proliferation and vascular remodeling. VEGF can also activate PDGF receptors. Hypoxia causes an increase in VEGF, Angiopoietin 1 (Ang1), and PDGF-B levels, which activate Akt and inhibit apoptosis, particularly in neurons.

Fig. 4. Hypoxia has heterogeneous effects on Receptor Tyrosine Kinase-independent vasotrophic factor signaling across various cell types

In perivascular nerves, hypoxia inhibits the synthesis and decreases the content of NE while enhancing serotonin (5-HT) synthesis. Elevated 5-HT levels can then induce proliferation of smooth muscle cells and increase prostacyclin levels, which inhibits ROS production and increase Ang2 production. Adenosine can activate A₂ receptors and inhibit proliferation while ATP enhances mitogenesis in SMCs but can also increase endothelial cell proliferation. Hypoxia enhances the expression of TGF-β, preproET-1 and ET-1 while inhibiting NO synthesis in endothelial cells. Hypoxia also enhances expression of both ET receptors in smooth muscle, thereby enhancing the effects of ET-1. Increased TGF-β2 levels enhance Smad2/Smad3 phosphorylation, which can then act as a coactivator for HIF-1. Angiotensin II activates AT₁, which leads to an increase in FGF-2, PDGF, TGF-β, and NADPH oxidase. Increased NADPH oxidase leads to enhanced ROS production, which can inhibit NO bioavailability and induce hypertrophy and hyperplasia of smooth muscle cells. ROS can also increase the gene expression of HIF-1α and stabilize the HIF-1α protein. The HIF-1 complex then enters the nucleus, binds HREs, and results in increased transcription of VEGF, VEGF receptors, and Ang II. The diagram includes separate depictions of mechanisms in neurons, smooth muscle cells, and endothelial cells. For reference, a generic (parenchymal) cell is depicted in the lower left corner.