Calcium dynamics and related alterations in pulmonary hypertension associated with heart failure
Congestive heart failure (CHF) represents an important Canadian health problem. Most patients with CHF develop pulmonary hypertension (PH), which is an important marker that signals progression of the disease and its poor outcome. Significant advances have been made for the treatment of heart failure (HF). Nevertheless, the morbidity and mortality among patients with advanced heart HF, who have developed PH remains high. Increased pulmonary vascular pressure (PVP) observed in PH leads to increased vascular tone and vascular remodelling associated with altered vasodilatory responses. It is noteworthy that a decrease in vasodilatory responses has been observed in PH. At the core of vasodilatory alterations lies endothelial dysfunction. This hallmark of most cardiovascular diseases is associated with alterations in calcium (Ca2+) homeostasis. Although global Ca2+ plays a role in a wide range of cellular functions, this thesis work focused on the impact of local Ca2+ signalling in endothelial cells (ECs). Among the different types of local Ca2+ signals, Ca2+ pulsars were identified. Ca2+ pulsars are local endothelial Ca2+ signals whose activity is finely regulated by physiological agents that modulate intracellular levels of inositol 1,4,5-triphosphate (IP3) and Ca2+. Ca2+ pulsars have been shown to have an effect on several important cellular functions. In mesenteric arteries, Ca2+ pulsars induce endotheliuminduced relaxation of vascular smooth muscle cells. Up until now, the regulatory mechanisms of Ca2+ pulsars remain to be uncovered. The spatio-temporal characteristics of Ca2+ pulsars suggest that they could play a role in the control of pulmonary vascular tone, potentially involving more transmembrane ion channels, as well as regulatory proteins. Transient receptor potential vanilloid 4 (TRPV4) channels are non-selective mechanosensitive osmo-regulated cation channels broadly expressed in a number of tissues. Activation of TRPV4 channels allows Ca2+ entry into the cell. A number of studies have shown the implication of TRPV4 as well as other channels from the TRP family in PH. Endothelial Ca2+-related pathophysiological mechanisms modulating pulmonary vascular tone and leading to the development of group II PH are poorly defined. In addition, the scarcity of studies exploring the pathophysiology and therapies of group II PH resides in the lack of validated small animal models with an adequate determination of the presence and severity of PH. The work in this thesis identified and characterized for the first time intracellular Ca2+ pulsars in pulmonary endothelium and their alterations in a clinically relevant mouse model of group II PH that was developed. In addition, this work revealed the implication of endothelial TRPV4 channels in Ca2+ pulsars dysregulation in group II-PH.
Pulmonary hypertension Heart failure Calcium Pulsars TRPV4