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Abstract
The majority of the conventional techniques that are utilized for investigating the pathogenesis of cardiovascular disease in preclinical animal models do not permit microlevel assessment of in situ cardiomyocyte and microvascular functions. Therefore, it has been difficult to establish whether cardiac dysfunction in complex multiorgan disease states, such as heart failure with preserved ejection fraction and pulmonary hypertension, have their origins in microvascular dysfunction or rather in the cardiomyocyte. Herein, we describe our approach of utilizing synchrotron radiation microangiography to, first, ascertain whether the growth hormone secretagogue (GHS) hexarelin is a vasodilator in the coronary circulation of normal and anesthetized Sprague-Dawley rats, and next investigate if hexarelin is able to prevent the pathogenesis of right ventricle (RV) dysfunction in pulmonary hypertension in the sugen chronic hypoxia model rat. We show that acute hexarelin administration evokes coronary microvascular dilation through GHS-receptor 1a and nitric oxide, and through endothelium-derived hyperpolarization. Previous work indicated that chronic exogenous administration of ghrelin largely prevented the pathogenesis of pulmonary hypertension in chronic hypoxia and in monocrotaline models. Unexpectedly, chronic hexarelin administration prior to sugen chronic hypoxia did not prevent RV hypertrophy or RV cardiomyocyte relaxation impairment. Small-angle X-ray scattering revealed that super relaxed myosin filaments contributed to diastolic dysfunction, and that length-dependent activation might contribute to sustained contractility of the RV. Thus, synchrotron-based imaging approaches can reveal novel insights into cardiac and coronary functions in vivo.
Highlights
The origins of cardiovascular disease have often been thought of as either being in the vasculature or in the myocardium, but more often than not, the techniques employed to investigate the origins of pathophysiological states that affect multiple organs are not sensitive enough to detect early changes in structure and in function in preclinical animal models
We have shown in prediabetic and diabetic rats that this approach is sensitive enough to detect impaired relaxation of in situ cardiomyocytes, regional differences in impairment across the left ventricle (LV) free wall, and changes in myosin thick filament activation that correlated with altered myofilament phosphorylation and protein kinase activity (Jenkins et al, 2013; Waddingham et al, 2015, 2019)
Hexarelin administration evoked a ∼20–40% increase in visualized vessels, principally in the third and fourth order branching both before and after the inhibition of nitric oxide and prostanoid production, while blockade with L-NAME and indomethacin itself did not change the visible number of vessels
Summary
The origins of cardiovascular disease have often been thought of as either being in the vasculature or in the myocardium, but more often than not, the techniques employed to investigate the origins of pathophysiological states that affect multiple organs are not sensitive enough to detect early changes in structure and in function in preclinical animal models. We propose that techniques utilizing synchrotron radiation (SR)-based hightemporal and -spatial resolution imaging, and X-ray diffraction in vivo provide an integrative approach to investigating vascular and myocardial roles in the pathophysiology of heart failure in small animal models on the micro- and nanoscales and are readily applied in combination with gold-standard cardiovascular techniques. These techniques have great potential to investigate the efficacy of potential pharmacological therapies and other interventions for heart failure. We briefly describe our motivation for directly assessing the physiological actions of this ghrelin analog in vivo
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