Traumatic brain injury (TBI) induces acute alterations in cerebral blood flow (CBF) autoregulation and cerebral artery contractility, which increases the risk of developing neurodegenerative diseases, as well as ischemic and hemorrhagic events. Progesterone modulates vascular tone in both males and females. Specifically, Progestin and adipoQ receptor family member 7 (PAQR7) is a plasma membrane progesterone receptor expressed in the arterial smooth muscle tissue of both animals and humans. Much of our knowledge of PAQR7 function comes from studying smooth muscle from conduit vessels (umbilical artery and vein) and has not been investigated in resistance size cerebral arteries that control local brain blood flow and tissue perfusion. While progesterone has successfully treated aspects of TBI in experimental models, this effect has failed to translate in human clinical trials, potentially due to its effects on multiple receptor subtypes. Here, we investigated the effects of TBI on the expression of PAQR7 and its smooth muscle vasodilatory action in cerebral arteries 24 hours following a moderately severe TBI in male Sprague Dawley rats. A combination of one-way and two-way ANOVA along with student’s t tests were used to examine statistical significance. Pressurized arterial myography of endothelium-denuded middle cerebral arteries exhibited robust vasodilation to pharmacological activation of PAQR7 (p<0.0001, n=6), adenylyl cyclase (p<0.0001, n=6), protein kinase A (PKA; p<0.0001, n=6), and protein kinase G (PKG; p=0.0021, n=6; one-way ANOVA). PAQR7-induced vasodilation (10-5M, p<0.005, n=6) was abolished with SQ 22536, an adenylyl cyclase inhibitor (p=0.9480, n=6), as well as cAMPS-Rp, a PKA inhibitor (p=0.7473, n=6), or Rp-8-pCPT-cGMPS, a PKG inhibitor (p=0.5123, n=6). Basal myogenic tone at physiological pressure (~70mmHg) was significantly lower in TBI as compared to sham arteries (p<0.0001; n=12), and KCl-induced vasoconstriction (60mM) was significantly attenuated in TBI arteries (p<0.0001; n=12). Neither total PAQR7 protein expression (Western blotting; p=0.5931, n=7) nor PAQR7 mRNA expression (qPCR; p=0.5751, n=7) was significantly affected by TBI. Pharmacological activation of PAQR7, adenylyl cyclase, PKA, and PKG all induced vasodilation in a concentration-dependent manner in sham arteries (10-9M to 10-5M); but this response was absent in arteries from TBI animals (p>0.05). While inhibitors of PKA and PKG had no effect on baseline myogenic tone, administration of an adenylyl cyclase inhibitor (10-5M, p=0.0360, n=6) significantly enhanced myogenic tone in sham arteries, but this effect was absent in TBI arteries. Moreover, PAQR7-induced vasodilation (10-5M, p<0.005, n=6) was abolished with inhibitors of adenylyl cyclase (10-5M, p=0.9480, n=6), but not PKA (10-5M, p=0.7473, n=6), or PKG (10-5M, p=0.5123, n=6) in sham arteries; however, inhibitors had no effect on PAQR7-induced vasodilation in TBI arteries (P>0.05). The results of the current study support a generalized state of arterial smooth muscle relaxation and resultant hyperemia (tissue hyperperfusion) 24 hours following TBI. Indeed, arterial responsiveness to components of vasodilatory signaling and vasoconstrictor capacity are attenuated following TBI. The concomitant attenuation of myogenic tone (larger resting diameter at physiological pressure) along with reduced vasoconstrictor capacity could render downstream capillary networks vulnerable to rupture. TBI-induced vasodilation (attenuation of smooth muscle arterial tone) may be targeted to mitigate the hyperemic phase of altered CBF and improve TBI outcome.
