Obesity is increasingly prevalent worldwide and has become one of the major health problems of modern society. Since 1980, the number of obese patients has doubled in >70 countries, with 107.7 million children and 603.7 million adults diagnosed with obesity in 195 countries in 2015 [1]. Obesity negatively affects metabolic homeostasis and is a risk factor for type 2 diabetes and atherosclerosis, which lead to cardiovascular disease and death [2]. Atherosclerosis is triggered by vascular endothelial disorders. Endothelial cells regulate vascular tone by balancing endothelium-dependent relaxation (EDR) and endothelium-dependent contraction (EDC) via vasoactive factors. In obesity, inflammation and oxidative stress cause endothelial dysfunction, resulting in decreased EDR and increased EDC, thereby leading to atherosclerosis and increasing the risk of cardiovascular disease [3, 4]. Thus, elucidation of the mechanism of endothelial dysfunction in obesity may lead to clinical applications for the prevention of cardiovascular disease.

TRP channels are a family of cation channels that act as cellular sensors to perceive changes in the external environment and convert this information into cation/Ca2+ influx. TRPC5, a member of the TRP channel family, is endogenously expressed in multiple cell types, such as vascular endothelial cells, vascular smooth muscle cells, cardiac myocytes, and arterial baroreceptor neurons. TRPC5 is reportedly involved in pathophysiologies such as atherosclerosis and cardiac hypertrophy, as well as in blood pressure regulation [5].

For example, the activation of TRPC5 channels reportedly prevented endothelial healing of arterial injuries in hypercholesterolemic mice [6]. In vascular endothelial cells, TRPC5 is also involved in vascular aging by regulating oxidative stress and the expression of sirtuin 1, a longevity gene [7]. Conversely, in aortic baroreceptor neurons, the TRPC5 channel is an important pressure transducer and plays an important role in maintaining blood pressure stability [8].

With respect to the tissue-specific regulation of the expression of TRPC5 in pathological conditions, the expression of TRPC5 is increased in monocytes in essential hypertensive patients compared to that in normotensive control subjects, along with an increased TRPC5-mediated Ca2+ influx [9]. Compared with normotensive Wistar-Kyoto rats, the expression of TRPC5 in the left ventricle was significantly higher in spontaneously hypertensive rats [10]. These results indicated that TRPC5 plays a potential role in the development of cardiovascular diseases.

In the current issue of Hypertension Research, Chu et al. demonstrated the pathophysiological significance of TRPC5 for EDC in obesity and its molecular mechanism (Fig. 1) [11]. Diet-induced obesity (DIO) mice exhibited enhanced TRPC5 expression in endothelial cells of the carotid arteries and stronger acetylcholine (Ach)-induced carotid artery constriction than normal-fat diet (NFD)-fed mice. Treatment with the TRPC5 inhibitor clemizole and TRPC5 gene deletion suppressed Ach-induced vasoconstrictor responses in DIO mice, indicating that TRPC5 mediates vasoconstriction in DIO mice. Furthermore, this vasoconstriction in mice was endothelium dependent, and TRPC5 contributed to Ach-induced Ca2+ influx in the endothelial cells of carotid arteries. TRPC5 is reportedly associated with EDC. Li et al. showed that EDR was significantly enhanced but EDC was markedly attenuated in aortic rings from aged mice with TRPC5 gene knockout compared with those from aged wild-type mice [7]. Furthermore, Liang et al. reported that TRPC5 in endothelial cells contributes to EDC by stimulating the production of cyclooxygenase (COX)-2-linked prostanoids using TRPC5 inhibitors and TRPC5 knockout mice [12]. However, the functional role of TRPC5 in EDC/EDR in obesity is unclear. The present study demonstrated that the expression of TRPC5 in vascular endothelial cells is significantly increased and contributes to EDC in a mouse model of obesity.

Fig. 1
figure 1

Increased TRPC5 expression promotes endothelium-dependent vasocontraction via the Ca2+/ROS/COX-2 pathway in obesity. ROS reactive oxygen species, COX-2 cyclooxygenase-2

In the present study by Chu et al., TRPC5-mediated EDC in DIO mice was decreased by inhibiting reactive oxygen species (ROS) [11]. In addition, COX-2 expression in the endothelial cells of carotid arteries was increased in DIO mice, and treatment with a COX-2 inhibitor suppressed Ach-induced vasocontraction. Furthermore, vasocontraction was suppressed in TRPC5-activated NFD-fed mice when the COX-2 inhibitor was added. These results indicate that TRPC5 induces EDC in the carotid arteries of DIO mice via the TRPC5/Ca2+/ROS/COX-2 signaling pathway. The present study provides novel insight into the pathophysiology of TRPC5-mediated EDC in obesity and further demonstrates that ROS are involved in the mechanism.

Liang et al. reported that TRPC5 promotes the COX-2-linked production of PGF2α, PGE2, and PGD2 and contributes to EDC [12]. However, in the carotid arteries of DIO mice in the present study, there was no significant increase in the major vasoconstrictors (cPLA2, PGF2α, PGE2, PGD2, PGI2, and 8-iso-PG) despite an increased Ca2+ influx. Relevant vasoactive factors have also been reported in previous studies of vascular regulation in obesity. Traupe et al. demonstrated enhanced endothelium-dependent prostanoid-mediated vasoconstriction and marked upregulation of the expression of the vascular thromboxane receptor gene in DIO mice [13]. In hypertensive patients, increased body mass index is reportedly associated with enhanced endothelin-1-dependent vasoconstrictor activity [14]. However, the present study did not identify vasoconstrictors that contribute to TRPC5-mediated EDC in obesity. In addition, the role of TRPC5 in hypertension is unknown because the present study was conducted in carotid arteries rather than in resistance arteries, which define blood pressure. Further studies are warranted to fully elucidate the vasoconstrictor mechanism of TRPC5 under obese conditions and for clinical applications.