The role of pulmonary vascular contractile protein expression in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is associated with refractory vasoconstriction and impaired NO-mediated vasodilatation of the pulmonary vasculature. Vascular tone is regulated by light chain (LC) phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosins, which are determined by the activities of MLC kinase and MLC phosphatase. Further, NO mediated vasodilatation requires the expression of a leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of MLC phosphatase. The objective of this study was to define contractile protein expression in the pulmonary arterial vasculature and vascular reactivity in PAH. In severe PAH, compared to controls, relative LZ+MYPT1 expression was decreased (100 ± 14% vs. 60 ± 6%, p<0.05, n=7-8), and NM myosin expression was increased (1 5 ± 4% vs. 53 ± 5% of total myosin, p<0.05, n=4-6). These changes in contractile protein expression should alter vascular reactivity; following activation with Ang II, force activation and relaxation were slowed, and sustained force was increased. Further, the sensitivity to ACh-mediated relaxation was reduced. These results demonstrate that changes in the pulmonary arterial SM contractile protein expression may participate in the molecular mechanism producing both the resting vasoconstriction and the decreased sensitivity to NO-mediated vasodilatation associated with PAH.

HFpEF, a Disease of the Vasculature: A Closer Look at the Other Half

“…The expression of LZþ/LZÀ MYPT1 decreases in heart failure [53][54][55] and pulmonary arterial hypertension. 56 Because a decrease in the expression of LZþ/LZÀ MYPT1 is associated with animal models of HFrEF, it is possible that there is also a decrease in LZþ/LZÀ expression in patients with HFpEF. Thus in HFpEF, a decrease in LZþ MYPT1 expression would contribute to the decrease in sensitivity to NO-mediated vasodilation and also increase vascular tone.…”

Hypoxia-Dependent Reactive Oxygen Species Signaling in the Pulmonary Circulation: Focus on Ion Channels

“…T he effects of alveolar hypoxia on the pulmonary circulation can be divided into three phases: (i) the acute phase (30 s to < 20 min), (ii) the sustained phase ( > 30-min to hours-days), which by hypoxic pulmonary vasoconstriction (HPV) matches blood perfusion to alveolar ventilation under conditions of regional alveolar hypoxia (163), and (iii) the chronic phase, which is characterized by refractory vasoconstriction (78) and vascular remodeling with media hypertrophy inducing pulmonary hypertension (PH) (Fig. 1).…”

Chronic hypoxia aggravates monocrotaline-induced pulmonary arterial hypertension: a rodent relevant model to the human severe form of the disease

“…In PAH, a resting vasoconstriction of pulmonary arteries contributes to the reduction in vascular caliber [21]. Altered reactivity of pulmonary arteries to vasoconstrictors such as endothelin-1, serotonin, angiotensin II, phenylephrine or PGF2α has been well documented in animal models of PH, in particular those induced by Hx or by MCT [12, 22, 23]. We show, in this study, that the model combining MCT administration to 4 weeks of Hx also reproduces and amplifies this aspect of PAH pathophysiology, and may therefore be helpful to further characterize the pathophysiological mechanisms of pulmonary arterial altered reactivity.

Fig.

…”