.... resistance is not futile ...
Resistance arteries are highly specialized structures. Their circularly-orientated smooth muscle cells allow for rapid changes in vessel diameter and hence, alterations in microvascular resistance and capillary perfusion. The intrinsic property of resistance arteries to antagonize an abrupt elevation in systemic blood pressure via an increase in vascular resistance (i.e., the myogenic response or Bayliss effect) plays an important role in the autoregulation of blood flow. In addition, the interplay between elevations in blood pressure (e.g., caused by augmented cardiac output) and the subsequent pressure-induced increases in peripheral resistance establishes a positive feedback mechanism, which can prominently contribute to an elevation in systemic blood pressure (hypertension). Despite its obvious importance in physiological and pathophysiological processes, our knowledge of resistance artery physiology is relatively limited.
Recently, our laboratory group has identified the endogenous lipid mediator sphingosine-1-phosphate (S1P) as a mandatory component of the signalling cascade that regulates vascular tone, myogenic vasoconstriction and Ca2+ sensitivity. Because of its pleiotropic biological/vascular effects, the bioavailability of S1P must be tightly regulated in a spatial-temporal manner. While our previous research supports an important role for S1P in the regulation of microvascular tone, little is known about the mechanisms that govern the dynamic equilibrium of S1P formation and degradation within the vascular wall of resistance arteries. Consequently, our research focuses on the characterization and regulation of two important enzymes that regulate S1P-bioavailability: sphingosine kinase 1 (Sk1) and S1P phosphohydrolase 1 (SPP1). We have recently provided evidence that Sk1 is a major determinant of microvascular reactivity. Most importantly, this enzyme is an integral part of the signalling cascade that leads to the initiation and maintenance of a myogenic vasoconstriction in response to increases in pressure. With regard to the SPP1, we already know that it is expressed at the level of mRNA in resistance arteries and that modulation of its expression affects responses to exogenously-applied S1P. Therefore, our future research aims to characterize the functional effects of SPP1 with respect to the regulation of vascular tone.
The primary focus of our research is to (i) identify endogenous modulators that activate pro-constrictive, Ca2+-independent pathways and their cellular and molecular mechanism of action; and (ii) to characterize their mode of action at the molecular level. Additionally, we have also initiated studies investigating significance of these mechanisms for different parts of the vascular tree (e.g. coronary, cerebral, skeletal muscle microcirculation). In this regard, we have recently demonstrated that S1P is of major importance for the regulation of inner ear blood flow and may, therefore, be involved in the pathogenesis of sudden sensoneurinal hearing loss (an "infarct of the inner ear").
In order to further define the cellular and molecular mechanisms by which the bioavailability of S1P is controlled, we will employ a model of cultured/transfected isolated resistance arteries. With this model, we can simultaneously measure intracellular Ca2+ and diameter, and combine them with several molecular and immunochemical approaches. Our research approach allows us to investigate novel and uncharacterized signalling pathways using genetically altered proteins in an intact artery. We believe that compared to cell cultures, this near in vivo system (which involves multiple interacting cells types) provides more physiologically relevant results. We hope that our platform considerably shortens the transfer of experimental results into an experimental in vivo situation, and ultimately, to clinical application
The knowledge gained from this type of research will ultimately help to better a mechanistic understanding of how S1P bioavailability is regulated within the vascular wall. As evidence regarding the importance of S1P in several cardiovascular pathologies mounts, this understanding is pivotal for the development of innovative treatment strategies.