HIF isoforms in the skin differentially regulate systemic arterial pressure

Abstract

Vascular flow through tissues is regulated via a number of homeostatic mechanisms. Localized control of tissue blood flow, or autoregulation, is a key factor in regulating tissue perfusion and oxygenation. We show here that the net balance between two hypoxia-inducible factor (HIF) transcription factor isoforms, HIF-1α and HIF-2α, is an essential mechanism regulating both local and systemic blood flow in the skin of mice. We also show that balance of HIF isoforms in keratinocyte-specific mutant mice affects thermal adaptation, exercise capacity, and systemic arterial pressure. The two primary HIF isoforms achieve these effects in opposing ways that are associated with HIF isoform regulation of nitric oxide production. We also show that a correlation exists between altered levels of HIF isoforms in the skin and the degree of idiopathic hypertension in human subjects. Thus, the balance between HIF-1α and HIF-2α expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.HIF-alpha | arginase | vascular tone A utoregulation of vascular flow in peripheral tissues is essential both for controlling local tissue perfusion and for the regulation of systemic blood pressure. This dual role for peripheral blood flow is dependent in turn on a range of factors that act to adjust local vascular tone. A key element of this control is the balance between O 2 demand and O 2 supply (1). This balance causes increased need for oxygen to induce increased blood flow. This regulatory pathway in peripheral tissues has a direct impact on systemic arterial pressure, because peripheral vascular resistance in large part determines total vascular resistance in the arterial bed.The skin contains a very extensive series of vascular plexi. This vascular bed has a range of essential functions, which include regulating body temperature. Skin circulation also is altered in a number of disease states, including renal disease (2), hypercholesterolemia (3), peripheral vascular disease (4), heart failure, and hypertension (5). Identification of structural alterations to the subcutaneous microvasculature provides a powerful prognostic tool to predict cardiovascular events in hypertensive patients (6), and impaired microvascular vasodilation and capillary rarefaction is associated with familial predisposition to hypertension (7).The heterodimeric transcription factors hypoxia-inducible factoralpha (HIF-1α) and HIF-2α are essential for the maintenance of cellular oxygen homeostasis (8). In response to hypoxia, stabilized HIF-1α and HIF-2α proteins initiate the expression of genes that alleviate hypoxic stress, including genes promoting cell growth, adhesion, and migration, new vessel formation, and the development of vascular networks (9,10).Recent data from a number of groups have indicated that HIF-1α and HIF-2α can act in a dualistic manner to regulate a range of responses in vivo; these interactions include functionally opposing interactions with the Myc t...

The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia

“…These results demonstrate that mitochondria act as oxygen sensors in vivo, promoting HIF activation and adaptation to hypoxic conditions. While it is unclear why deletion of VHL in the epidermis resulted in early mortality, it was recently shown that in addition to regulating hypoxic adaptation, epidermal HIF levels regulate systemic arterial pressure and thermoregulation in mice (Cowburn et al, 2013). Thus, our results add to the increasing evidence for the importance of oxygen sensing and HIF activation within the epidermis for organismal homeostasis.…”

Human high-altitude adaptation: forward genetics meets the HIF pathway

“…For example, HIF-1a promotes cell cycle arrest, whereas HIF-2a promotes progression through the cell cycle, likely in a cell context-dependent manner (Keith et al 2012). In murine macrophages, keratinocytes, and endothelial cells, Hif-1a promotes NO production through activation of the inducible NO synthase (Nos2) gene, whereas Hif-2a inhibits NO production through the induction of the arginase (Arg) gene Branco-Price et al 2012;Cowburn et al 2013). Finally, Hif1a +/À mice display blunted respiratory responses to chronic hypoxia, while Hif2a +/À mice display exaggerated carotid body sensitivity to hypoxia ( Fig.…”

Tissue sodium storage: evidence for kidney-like extrarenal countercurrent systems?

“…Johnson and colleagues have demonstrated that the two hypoxia-inducible factor (HIF) transcription factors HIF-1α and HIF-2α critically control the NO equilibrium in the skin, with keratinocyte-HIF-2α promoting vascoconstriction, while keratinocyte-HIF-1α mediates vasodilation [5]. Mice with keratinocyte-specific deletion of HIF-1α therefore had higher blood pressure, while HIF-2α deletion resulted in low blood pressure levels and body temperature loss.…”