NOTCH3, a member of the Notch family, is a highly conserved gene that regulates cell-cell interaction, embryogenesis, and tissue commitment [4]. Its receptor signaling is linked to the regulation of smooth muscle cell proliferation and maintenance in an undifferentiated state, and is critically involved in vascular development and differentiation, especially as it is almost exclusively expressed in vascular smooth muscle cells (VSMCs) [2,3]. The NOTCH signaling pathway, in which NOTCH3 participates, plays important roles in various biological processes including lung development, differentiation, and regeneration post-injury [5].

NOTCH3 mutations have been identified as the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common hereditary cerebral small vessel disease (CSVD) [1,8,9]. In CADASIL, it is hypothesized that structural abnormalities in the vascular smooth-muscle protein NOTCH3 due to mutations trigger arterial degeneration, vascular protein accumulation, and cerebrovascular failure [9]. Also, in pulmonary arterial hypertension (PAH), abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of the disease. Animal models have shown the importance of the Notch3 pathway in clinical PAH [2,3]. In cancer, Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy, with its role mainly oncogenic, although in some cancers it appears to be tumor suppressive [4,7]. In bladder cancer, NOTCH3 promotes malignant progression by directly regulating SPP1 and activating the PI3K/AKT pathway [6].

In conclusion, NOTCH3 is crucial for normal vascular development and differentiation, and its dysregulation is associated with multiple diseases such as CADASIL, PAH, and various cancers. Studies using animal models, especially in the context of CADASIL and PAH, have been instrumental in revealing the role of NOTCH3 in disease pathogenesis, providing insights for potential therapeutic strategies targeting this gene in these disease areas.

References:

1. Yuan, Lamei, Chen, Xiangyu, Jankovic, Joseph, Deng, Hao. 2024. CADASIL: A NOTCH3-associated cerebral small vessel disease. In Journal of advanced research, 66, 223-235. doi:10.1016/j.jare.2024.01.001. https://pubmed.ncbi.nlm.nih.gov/38176524/

2. Winicki, Nolan M, Puerta, Cristian, Besse, Casandra E, Zhang, Yu, Thistlethwaite, Patricia A. 2024. NOTCH3 and Pulmonary Arterial Hypertension. In International journal of molecular sciences, 25, . doi:10.3390/ijms25116248. https://pubmed.ncbi.nlm.nih.gov/38892440/

3. Morris, Hannah E, Neves, Karla B, Montezano, Augusto C, MacLean, Margaret R, Touyz, Rhian M. . Notch3 signalling and vascular remodelling in pulmonary arterial hypertension. In Clinical science (London, England : 1979), 133, 2481-2498. doi:10.1042/CS20190835. https://pubmed.ncbi.nlm.nih.gov/31868216/

4. Aburjania, Zviadi, Jang, Samuel, Whitt, Jason, Chen, Herbert, Rose, J Bart. 2018. The Role of Notch3 in Cancer. In The oncologist, 23, 900-911. doi:10.1634/theoncologist.2017-0677. https://pubmed.ncbi.nlm.nih.gov/29622701/

5. Bodas, Manish, Subramaniyan, Bharathiraja, Karmouty-Quintana, Harry, Vitiello, Peter F, Walters, Matthew S. 2022. The emerging role of NOTCH3 receptor signalling in human lung diseases. In Expert reviews in molecular medicine, 24, e33. doi:10.1017/erm.2022.27. https://pubmed.ncbi.nlm.nih.gov/36052538/

6. Liu, Changxue, Ge, Huaixi, Shen, Chengquan, Qin, Ruize, Wang, Yonghua. 2024. NOTCH3 promotes malignant progression of bladder cancer by directly regulating SPP1 and activating PI3K/AKT pathway. In Cell death & disease, 15, 840. doi:10.1038/s41419-024-07241-0. https://pubmed.ncbi.nlm.nih.gov/39557868/

7. Bellavia, Diana, Checquolo, Saula, Palermo, Rocco, Screpanti, Isabella. . The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms. In Advances in experimental medicine and biology, 1066, 205-222. doi:10.1007/978-3-319-89512-3_10. https://pubmed.ncbi.nlm.nih.gov/30030828/

8. Mizuta, Ikuko, Nakao-Azuma, Yumiko, Yoshida, Hideki, Yamaguchi, Masamitsu, Mizuno, Toshiki. 2024. Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease. In Biomolecules, 14, . doi:10.3390/biom14010127. https://pubmed.ncbi.nlm.nih.gov/38254727/

9. Wang, Michael M. . CADASIL. In Handbook of clinical neurology, 148, 733-743. doi:10.1016/B978-0-444-64076-5.00047-8. https://pubmed.ncbi.nlm.nih.gov/29478611/