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Title: Cardiovascular adaptation to hypoxia and the role of peripheral resistance}
Article:
Abstract:
Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia.
Introduction:
Vertebrates confront the world chiefly through the skin. As a reflection of how different vertebrates adapt to the environment, skin structure varies to a significant degree from one vertebrate class to another, and even within classes. One of the key differences in skin function found amongst vertebrates is the degree to which it responds to environmental variations; in particular, the extent to which these changes in turn affect systemic organismal physiology. Mammalian skin is amongst the most complex of all the vertebrate forms of skin. It also varies significantly in its form in the different orders of mammalia, with variations chiefly following adaptations to the external environment. A key physiological challenge faced by most multicellular organisms is variation in oxygen supply. This is a common challenge to animals that obtain their oxygen from surrounding water, particularly those that live in fresh water; it can apply also to mammals at high altitudes, or during movement into a small den or confined space. Hypoxia also occurs in various tissues if there are high levels of oxygen demand, e. g., in skeletal muscle during exercise. Work undertaken over the last 50 years has shown that acute systemic hypoxia in mice, rats, rabbits, chickens, dogs, sheep and humans causes acute tachycardia and hypertension( Korner and Edwards, 1960; Butler, 1967; Yasuma and Hayano, 2000; Campen et al., 2004; Campen et al., 2005; Walsh and Marshall, 2006; Heinonen et al., 2016; Giussani et al., 1993; Fletcher, 2000). Prolonged hypobaric hypoxia in humans has also been shown to cause tachycardia and hypertension( these studies have primarily been undertaken in high altitude environments or models thereof)( Schultz et al., 2014; Calbet, 2003; Naeije, 2010; Hainsworth et al., 2007; Vogel and Harris, 1967). The skin has an extensive vasculature, which is known to be responsive to shifts in oxygen availability( Durand et al., 1969; Weil et al., 1969; Kuwahira et al., 1993; Minson, 2003). Keratinocytes in low oxygen release nitric oxide to increase blood flow and thereby improve perfusion( Cowburn et al., 2013; Pucci et al., 2012). Of interest, it has been shown that in both rodents and humans the basal epidermis is hypoxic relative to the underlying dermal tissue, and displays constitutive stabilisation of hypoxia inducible transcription factor-( HIF) α proteins( Cowburn et al., 2013; Cowburn et al., 2014; Peyssonnaux et al., 2008; Boutin et al., 2008). HIF transcription factors initiate the transcription of multiple genes involved in oxygen homeostasis, including a number that regulate vascularisation and metabolism( Semenza, 2003; Semenza, 2009; Pouysségur et al., 2006; Formenti et al., 2010; Djagaeva and Doronkin, 2010; Hubbi et al., 2014). We have previously shown that a dichotomous regulation of nitric oxide is conferred by HIF-1α and HIF-2α regulation of the NOS2 and arginase genes( Semenza, 2003; Jung et al., 2000) and have now documented this in a number of tissues and cell types( Cowburn et al., 2013; Takeda et al., 2010; Branco-Price et al., 2012; Cowburn et al., 2016). The HIF-1α/NOS2 and HIF-2α/arginase pathways strongly influence tissue L-arginine consumption and NO generation( Cowburn et al., 2013; Takeda et al., 2010; Branco-Price et al., 2012). We have also shown that keratinocyte selective deletion of HIF-1α reduces epidermal NO levels, whereas loss of HIF-2α suppresses arginase expression/activity, increasing local concentrations of NO( Cowburn et al., 2013). Hence, in murine skin, cutaneous NO levels are determined by differential HIFα isoform expression which affect both local vascular resistance and systemic blood pressure. Little is known, however, concerning how a localized tissue response to hypoxia affects the cardiovascular system more generally. The literature on the response of animals to systemic hypoxia and its cardiovascular effects is limited almost exclusively to studies under anaesthesia. Hence, almost all previous studies have focused on the first ten minutes of the hypoxic response. Radio-telemetry in non-anesthetised non-restrained animals allows a more rigorous evaluation of the changes in hemodynamic variables during the acclimation to environmental hypoxia( Kawaguchi et al., 2005). The work described here demonstrates for the first time that systemic hypoxia induces a tri-modal response: with an initial tachycardia and hypertensive phase that lasts approximately 10 min, followed by an immediate and profound drop in heart rate and blood pressure that can last as long as 24 hr, followed by a recovery to close to a normoxic state. In this context, we show that peripheral resistance and oxygen sensing, in this case in the skin, plays an essential role in this systemic cardiovascular response. These data demonstrate that peripheral tissues can play a fundamental role in cardiovascular adaptation to hypoxia.
Discussion:
We believe that this is the first detailed investigation of cardiovascular acclimatization to hypoxia in mice over the time frames used here. Although there have been a number of previous studies examining cardiovascular hypoxic response, these have either ended after approximately ten minutes of observation and used anaesthesia, or have involved long term exposures, with monitoring after days or weeks of conditioning( Campen et al., 2004; Campen et al., 2005). Here, we monitored animals breathing 10, 12, 15, and 21% FiO2 for 48 hr, followed by a 24 hr recovery period. We found that mice exhibited a well-documented elevation of heart rate and blood pressure for the first ten minutes of exposure to hypoxia( Campen et al., 2004; Yu et al., 1999; Dematteis et al., 2008; Pearson et al., 2007), but then, experience a dramatic drop in both parameters. The maximal negative deflection in heart rate and blood pressure was observed at 3 hr post-onset of hypoxic exposure, which coincided with increased peripheral vascular resistance, and very low physical activity. Cardiovascular parameters were approximately restored to normoxic levels over the next 45 hr. These paths of decline and recovery are striking adaptive responses to hypoxia, and they appear to be graded relative to the degree of hypoxic challenge. The processes controlling cardiovascular responses to hypoxia are complex, and include chemoreceptors and baroreceptors as part of an autonomic nervous system reflex. These neurally-mediated responses also interact with, and may frequently mask, local tissue effects of hypoxia on cardiovascular responses, making it difficult to dissociate extrinsic and local tissue responses( Bärtsch and Gibbs, 2007). We have previously documented that a balance in keratinocyte HIF-1α and HIF-2α expression modulates peripheral vascular resistance( Boutin et al., 2008), and that this directly affects murine systemic blood pressure; it is also correlated with the tonic tensive state in mildly hypertensive humans( Cowburn et al., 2013). Here we show for the first time that keratinocyte HIF-1α and HIF-2α expression affects the immediate, acute and chronic phases of the cardiovascular response to hypoxia. Hypoxia immediately heightens sympathetic tone in the skin to increase peripheral vascular resistance( Simmons et al., 2007; Chalmers and Korner, 1966; Kollai, 1983). Hypoxia also increases nitric oxide release from keratinocytes to stimulate vasodilation and act as a neuromodulator of sympathetic activity, dampening vasoconstriction( Ramchandra et al., 2005; Sartori et al., 2005; Hirooka et al., 2011). The opposing roles of keratinocyte HIF-1α and HIF-2α on nitric oxide synthesis( Cowburn et al., 2013) would suggest divergent effects on sympathetic activity and blood flow in this highly vascular tissue. Epidermal HIF-1α is shown here to have a direct effect on peripheral vascular resistance and the tonic tensive status of the mouse. The opposite cardiovascular relationship is apparent in the HIF-2α mutant mouse. In the case of the HIF-2α mouse, however, there is a significant increase in heart rate, likely to maintain systolic blood pressure. In this mutant, there appears to be a transition/acclimation checkpoint following 24 hr in hypoxia. The heart rates of both HIF-2α mutant and littermate mice converge at this point, and systolic pressure of the HIF-2α mutant drops below that of controls. This suggests a sustained decrease in the vascular resistance of the skin. Epidermal deletion of arginase-1 in this hypoxia acclimation model phenocopied several characteristics of the K14cre-HIF-2α mutant mouse. There is an overall lessening of the effect, however, indicating that other genes controlled by HIF-2α are likely involved in the hypoxic acclimation process. These alterations in peripheral vascular blood flow also appear to affect whole body metabolism and physical activity during the acclimation phase to hypoxia. Although all four epidermal mutant mice described here demonstrated a similar increase in oxygen consumption during this acclimation phase, only K14cre-HIF-2α and K14cre-arginase-1 mice demonstrated some preservation of physical activity in comparison to wild-type animals. This is intriguing, as it indicates that the response of the peripheral tissue can modulate the animals overall behaviour during environmental stress. Interestingly, the data presented here are consistent with cardiopulmonary investigation of patients with germline, heterozygous gain-of-function mutations in HIF-2α, where baseline heart rate and cardiac responses to moderate hypoxia were shown to be higher in the HIF-2α-gain of function patients when compared to control subjects, suggesting an increase in cardiac sympathetic tone( Formenti et al., 2011). In summary, we present here the first dissection of the murine cardiovascular response to hypoxia, and we present evidence that this response is highly influenced by peripheral vascular responses. This indicates that peripheral tissues, and their vascular beds, form a complex physiological network of oxygen-responsive tissues that influence, and are not just influenced by, central regulators of cardiovascular function. This interaction amongst tissues indicates that cardiovascular responses to hypoxia are likely a summation of a range of tissue responses, and not solely dictated by central mediators of cardiovascular activity.
Diseases of the heart and blood vessels are linked with high blood pressure . The causes of most cases of high blood pressure are unknown , but it is often accompanied by the reduced flow of blood through small vessels in the skin and other parts of the body that are a long way from the heart . It is not clear why this change happens or why it tends to get worse over time in people with high blood pressure that has not been treated . Previous research has shown that when a tissue is starved of oxygen , blood flow to that tissue will increase . The HIF family of proteins help to increase blood flow to tissues in these low-oxygen situations . To investigate what role the skin plays in the flow of blood through small vessels , Cowburn et al . exposed mutant mice that cannot produce certain HIF proteins specifically in the skin to low-oxygen conditions . The experiments show that mice lacking either HIF-1α or HIF-2α in the skin have altered responses to oxygen starvation that affected their heart rate , blood pressure , skin temperature and general levels of activity . Mice lacking specific proteins controlled by the HIFs also responded in a similar way . Cowburn et al . also demonstrated that the way normal healthy mice respond to oxygen starvation is more complex than previously thought . Blood pressure and heart rate rise in during the first ten minutes . This is followed by a period of up to 36 hours where blood pressure and heart rate decrease below normal levels . By around 48 hours after exposure to low levels of oxygen , blood pressure and heart rate recover , returning to normal levels . Loss of the HIF proteins or other proteins involved in the response to oxygen starvation specifically in the skin affect when this process starts and how long it takes . These findings suggest that the responses of the skin to environmental challenges may have substantial effects on the how the heart pumps blood around the body . More studies are needed to understand how the HIFs and other proteins may contribute to high blood pressure and diseases affecting the heart and blood vessels .